Microsoft did not explain why Windows president Steven Sinofsky was departing, but Windows 8 has had a mixed reception since its launch on October 26.
Chief executive Steven Ballmer said: "I am grateful for the many years of work that Steven has contributed to the company.
"The products and services we have delivered to the market in the past few months mark the launch of a new era at Microsoft.
"To continue this success it is imperative that we continue to drive alignment across all Microsoft teams, and have more integrated and rapid development cycles for our offerings."
Products launched in recent months include Windows 8, new Windows-powered mobile phones, a Surface tablet computer and the Halo 4 video game that is exclusive to Microsoft's Xbox 360 console.
Mr Sinofsky's duties are being divided between a pair of executives who will answer directly to the CEO.
Julie Larson-Green has been promoted to lead Windows software and hardware engineering, while chief financial officer Tami Reller will run the business side of Windows in addition to her current duties.
"It is impossible to count the blessings I have received over my years at Microsoft," Mr Sinofsky said in a written statement.
"I am humbled by the professionalism and generosity of everyone I have had the good fortune to work with at this awesome company."
Mr Sinofsky joined Microsoft in 1989 as a software engineer and became head of the Windows team in 2009.
Microsoft kicked off sales of its revamped Windows 8 system and Surface tablet late last month as it accelerated its efforts to compete in a market shifting rapidly from PCs to mobile devices.
More From Sky News