San Francisco Mayor Ed Lee died just after 1 a.m. local time at Zuckerberg San Francisco General Hospital, the San Francisco Examiner reports.
"It is with profound sadness and terrible grief that we confirm that Mayor Edwin M. Lee passed away on Tuesday, December 12 at 1:11 a.m. at Zuckerberg San Francisco General Hospital. Family, friends and colleagues were at his side," his office said in a statement, according to the Examiner.
"Our thoughts and prayers are with his wife Anita, his two daughters, Brianna and Tania, and his family."
Lee will be succeeded by San Francisco Board of Supervisors President London Breed. Lee was originally appointed by the board as mayor in 2011, and won reelection in 2015.
As recently as last week, Lee joined his "Fix-It Team" cleaning up the streets of the city and addressing quality of life issues.
Lee presided over San Francisco during pivotal years when Silicone Valley giants took off and revolutionised industry while causing home prices in his city to skyrocket.
But Lee's run as mayor ran into international controversy recently, when he accepted a statue from South Korea commemorating the "comfort women" who the Japanese military used as sex slaves during World War II.