Instead of fashion models, the edition -- which will be released on October 6 -- will feature academics, CEOs and entrepreneurs clad in the latest designer clothes.
Editor Alexandra Shulman said she came up with the idea for the "Real Issue" earlier this year when she had trouble finding designer samples that would fit non-models.
"I though it would be interesting for us to put together an issue of the magazine ... where we looked in various ways at the subject of what we wear through a more "real" filter," she said.
Shulman, who has been editor of Vogue since 1991, said women no matter their age, size or profession, "should be able to be seen to enjoy the vagaries of fashion in style."
Many commentators welcomed the move and praised Shulman for her efforts to set a positive example. However, others questioned the differentiation between "real" women and models, and wondered how effective one such edition can be -- especially when the "real issue" cover girl is British actress, Emily Blunt.
Plus size fashion blogger Bethany Rutter
told CNN that while it's important to address the way women are perceived in mainstream media, Vogue's intentions may be counterintuitive.
"Any kind of special edition, or short term tick box exercise ends up maybe being worse," she said. "It means the magazine can kick back and say: Well we did that issue, we've done our bit."
Rutter said instead she'd prefer to see "real" models integrated constantly throughout magazines and on television.
"I think de-focusing on features about dieting and not only presenting very thin women would be useful," she said.
Editor Schulman acknowledged changing the way women are presented was not an easy task.
"But it's not simple, and the combination of a newspaper commentariat -- which is always keen to leap critically on a woman in the public eye who dresses even the slightest bit adventurously -- alongside a professional culture that still encourages a conventional conformity, makes it hard for some women to dress the way they would really like to," she said.
The magazine, which goes on sale from October 6, will include a series of features addressing what "real" is and the wardrobes of professional women.
However even actress Emily Blunt, who's on the cover of the issue, joked: "It took three hours of hair and make-up to get me looking this real!"