Steven Sinofsky, the head of Microsoft's Windows division, has left the company with immediate effect.
Sinofsky's departure on Tuesday comes just weeks after the software company launched Windows 8, which represented a major overhaul of its popular computer operating system.
Microsoft did not give any reason for Sinofsky's departure, but confirmed that company veteran Julie Larson-Green has been promoted to lead all Windows software and hardware engineering.
Tami Reller will take over responsibility for the Windows business while retaining her posts as chief financial officer and chief marketing officer.
In a statement, Microsoft CEO Steve Ballmer expressed gratitude for Sinofsky's contribution to the company.
He indicated the need for the company to further integrate its array of offerings, which in addition to Windows includes services such as Bing, Skype and Xbox and a new tablet computer, as it begins what he called "a new era at Microsoft".
Ballmer said "it is imperative that we continue to drive alignment across all Microsoft teams, and have more integrated and rapid development cycles for our offerings".
The launch of Windows 8 last month heralded the biggest change to the industry's dominant operating system in at least 17 years. It attempts to bridge the gap between personal computers and fast-growing tablets with its touch-enabled interface.
Sinofsky joined Microsoft as a software design engineer in 1989. Before heading the Windows division, his work included overseeing the development of Microsoft Office products.