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Alexander Zverev defeated Matteo Berrettini in the final, 6-7(8-10), 6-4, 6-3 to win the men's singles tennis title at the 2021 Madrid Open. It was Zverev's fourth ATP Masters 1000 title, his first since winning Madrid in 2018, and his 15th career ATP Tour singles title overall. Berrettini was in contention to become the second Italian to be crowned a Masters 1000 champion in his first final at this level.
Novak Djokovic was the defending champion from when the tournament was last held in 2019, but announced his withdrawal prior to the event.