With Spanish riders occupying 10 of the 23 spaces on starting grid, it will be a homecoming for almost half of the premier-class riders.
It will also be a stark contrast to the previous race in Austin, Texas, where not a single American racer could be found in any of the three classes.
At the stunning Circuit of the Americas, curled around an undulating stretch of scrubland on the city's outskirts, there were reminders of America's golden age, with four of its most successful racers present at the track.
With US stalwarts Wayne Rainey, Kevin Schwantz, Kenny Roberts and his son Kenny Roberts Jr. standing by, CNN Sport asked the question: Just what's happened to all the great Americans in MotoGP?
It's the money
Kenny Roberts Jr., who was celebrating his induction into the MotoGP Hall of Fame, acknowledges that having a world-champion father gave him a distinct advantage.
"I raced and practiced with world champions at a very young level, so it gave me an understanding of where I eventually needed to be," he told CNN.
"I knew everything it took instead of wondering what it took, if that makes sense."
The 43-year-old believes entering the sport now is tougher than ever. Part of the reason, he says, is financial.
"I think it's much harder to get into now. The bikes are very close and the first top of the class in Moto3 are getting paid, but the last half -- even three quarters -- aren't making money.
"They're bringing money to a team ... and when you start doing that it's very difficult I think."
Behind the curve
Kevin Schwantz, the 1993 world champion who helped design the Austin circuit, believes Americans are at an immediate disadvantage compared with their European rivals.
"It's very difficult for American kids to get into the world championship loop," he told CNN. "I mean, Italy, Germany, Spain, everybody's got their pre-Moto3 championships, young kids can get there and start riding when they're 13 or 14."
He points to one emerging American star who could break through, although he has had to travel to Europe to do it.
"We've got this kid, Damian Jigalov, in Italy racing and he's 12 years old, riding at 300 km/h, and he's better than anyone else on the track," added Schwantz.
"He's going to Europe, and doing races, and opening people's eyes a little bit."
However, most American riders, Schwantz says, are behind the curve before they even start.
"I think our problem here is that most of us don't think our kids can do anything until they're 16, when they can come race in MotoAmerica and be a professional," he explained.
"If you're not on tracks where Grands Prix are being raced by the time you're 16 you're well behind the Europeans, because they've been there for a couple of years by the time they're that age and it's just such an easy transition."
Carmelo Ezpeleta, head of MotoGP administrator Dorna, believes the absence of a feeder championship in the US is a key reason American talent is no longer breaking through.
"One big factor is the disappearance of the AMA Superbike series, because national competition has a great effect on creating champions in every country," he told CNN.
"Now there is MotoAmerica, and it's been a long time since there was a championship of that caliber to showcase and develop talent within the US."
Not that he doesn't believe things will improve.
"Now we hope the situation will begin to change and we will again see American talent emerging onto the global stage," said Ezpeleta.
"It is certainly something that must be addressed because a lack of a national championship means a lack of new riders. I am sure there will be great American champions in the future again, just as there were in the past."
Ezpeleta would also like to see a new junior series in the US.
"An American Talent Cup could be the future for talent discovery and promotion in North America," he said.
"Something similar to the Asia Talent Cup or the soon-to-start British Talent Cup. One of the key things upon which the future of the sport depends is the talent and the riders, because they create so much of the show -- one of the greatest on Earth."
A 15-year project
Roberts Jr. acknowledges Dorna's efforts, but believes the US may have a long wait before its riders repopulate the MotoGP grid.
"To get Americans back into it, it's got to be an entire team effort," he told CNN. "It's like the Olympics -- you don't want just Spaniards and Italians and so on, it has to be an entire mix.
"I know Dorna is making a big push to make sure young talent is coming through the field in other countries, and that's what they have to do here. That's a 15-year building block, in my opinion."
A team of 50
Another issue for racing is the gulf in funding between MotoGP and other championships.
"My dad and mom went to have a tour of the KTM garage with Tim Kopra, the astronaut, and he said: 'I can't believe it, a two-rider team has close to 50 people!'" Schwantz told CNN.
"We were talking to Howard Plumpton, who was the coordinator for Team Suzuki when I raced there, and he said, 'at our biggest, we were nine.' I mean, just the airfare getting people wherever you've got to get them, has quadrupled the budget."
By contrast, Schwantz says, MotoAmerica struggles for cash.
"What else that's lacking here in America is the support from the manufacturers," the former Suzuki rider told CNN.
"There's no real sponsors -- outside sponsors -- involved in MotoAmerica, so no real manufacturer support, and for sure without the sales of motorcycles and sports bikes where they used to be, you're not going to get a Suzuki spending $10 million racing."
America still loves bikes
Schwantz also points to a decline in interest in sports bikes on the streets of US, telling CNN it's become more about the "vintage scene."
"The guys at Revival here in Austin have hit the nail on the head, taking an old, beat-up bike that looks to be something you wouldn't even wanna ride, and turning it into a daily commuter bike," said Schwantz.
As he puts it, that couldn't be further from splashing out "$20,000 to go buy a sport bike that you can barely use second gear on in most cities."
Again, Schwantz points to the contrast with Europe, telling CNN: "They buy scooters, they ride them in the winter, ride them in the summer -- it is their means of transportation.
"Parking is a whole lot easier with a motorcycle," he added. "How much easier would it be here if we could get motorcycles to be commonplace as a means of transportation?"
On race day, the Austin circuit was packed, indicating that MotoGP's appeal in the US remains strong.
But Schwantz believes the spectator experience could be improved, telling CNN he would "try and make things more accessible to the average person that comes, not just the person that has the paddock pass."
Schwantz understands the pressure on riders like Valentino Rossi to spend time with fans, but recalls his first interactions with spectators as a young racer, when veteran competitor John Ulrich told him he'd quickly get tired of signing autographs.
The older rider told Schwantz: "what you're really gonna hate is when they don't want them anymore, so sign as many as you can."
Life after Rossi
Away from the dearth of Americans, there's no doubt championship leader Valentino Rossi's appeal remains a huge part of MotoGP's popularity, and the prospect of life after the charismatic Italian is another big question for the sport.
In Austin, crowds of fans waited patiently for a glimpse of the seven-time world champion, whose popularity way exceeds anyone else on the grid.
But Schwantz is optimistic about the future, telling CNN: "I think as long as the racing continues to be as good as it is in all three classes, there will be that next kid who stands out in Moto3 and turns into the next Valentino.
"I don't think there's anyone right now -- I think (the late) Marco Simoncelli was that guy.
"Maybe there will be a drop in attendance initially, but when everybody realizes the racing is still as good as it's ever been, and that all it takes is a little bit of mist, a little bit of rain, and anybody in the field could win ... I think MotoGP is in a good place right now."
Roberts Jr. jokes Rossi "has to ask" him permission to retire.
"I have to give it my blessing," smiled the 2000 championship winner. "Maybe that's what he's been waiting for, maybe he's been waiting for me to tell him he can stop. I hope he doesn't.
"He was talking about going until he's forty, so a couple more years of him would be great."