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Mr Sinofsky oversaw the launch of Windows 8 the latest edition of its flagship product
His departure comes just weeks after Microsoft launched Windows 8, the latest edition of its flagship product, seen as key to the firm's future.
Microsoft did not give any reason for Mr Sinofsky's departure.
The company said Julie Larson-Green would be promoted to lead all Windows software and hardware engineering.
"This is shocking news. This is very surprising," said Brendan Barnicle, an analyst at Pacific Crest Securities.
He added that many observers saw Mr Sinofsky as a potential successor to Steve Ballmer, Microsoft's chief executive.
'A new era'
Mr Sinofksy's departure is the latest change at the top of some of the world's biggest technology companies.
Last month, Apple announced that Scott Forstall, head of its iOS software, and John Browett, head of retail, would be leaving the firm.
The announcement followed problems with Apple's new mapping software and disappointing quarterly results.
Meanwhile,Yahoo - which has been trying to regain some of its lost market share - also hired a new chief operating officer in October.
In July the internet company appointed its third chief executive in a year.
"The pace at which changes are happening in the industry is so intense that companies are struggling to keep up with it," Manoj Menon of consulting firm Frost & Sullivan told the BBC.
"Business models are changing, competition is coming from unexpected quarters and economic challenges are only getting tougher.
"The changes in leadership are a reflection of these trends and the uncertainties around what will drive future growth and profitability," he added.
Microsoft's Mr Ballmer said the changes in leadership were aimed at ensuring the firm continued to be a dominant player in the sector.
"The products and services we have delivered to the market in the past few months mark the launch of a new era at Microsoft," Mr Ballmer said.
"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."