Mathews, who has been with the company for 22 years, will work closely with chief operating officer Kevin Turner to ensure a smooth transition while her successor is identified.
In her role as senior vice president of the central marketing team, Mathews oversees the company's communications around products including its Windows and Windows Phone 7 software, search engine Bing, music player/service Zune and games console Xbox.
One likely candidate to succeed Mathews is Yusuf Mehdi, senior vice president of Microsoft's online audience business, according to influential US blog All Things Digital.
In a statement, Microsoft said: "Mich has been instrumental in driving growth of the Microsoft business while also building the Microsoft brand, which consistently has placed in the Top 10 of many brand strength and image indicators.
"We would like to extend our deepest thanks to Mich for her many contributions during a time of incredible growth and change for Microsoft and the industry."
Microsoft's UK advertising spend totalled £36.7m last year, according to Marketing's Top 100 Advertisers data.