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It comes less than two weeks after they made their last public appearance, virtually, at a COVID event for healthcare workers.
The 65-year-old Microsoft founder and his 56-year-old wife announced the split on Twitter, where they both posted the same joint statement.
Gates, the fourth richest man in the world with a net worth of $130bn (£93bn), married Melinda in January 1994.
The couple has together emerged as leading figures in the global fight against Covid-19, and their separation is likely to send shock waves through the worlds of philanthropy, public health, and business.
The couple has three kids; Jennifer, 25, Rory, 21, and Phoebe, 18.
The divorce will create new questions about the fate of the Gates fortune, much of which has not yet been donated to the Bill and Melinda Gates Foundation. Mr. Gates, who co-founded Microsoft, is one of the richest people in the world, worth an estimated $124 billion, according to Forbes.
In 2019, shortly after their 25th wedding anniversary, Melinda, in a rare interview, told The Sunday Times that Bill struggled with balancing work with family.