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Rafael Nadal defeated the defending champion Novak Djokovic in the final, 7-5, 1-6, 6-3 to win the men's singles tennis title at the 2021 Italian Open. It was his record-extending 10th Italian Open title and record-equaling 36th Masters 1000 title overall (matching Djokovic's tally). Nadal saved two match points en route to the title, in his third round match against Denis Shapovalov. This was also the fourth time that Nadal had won a tournament on 10 or more occasions, making him the only tennis player with the feat.
It was Djokovic's sixth runner-up finish at the Italian Open, a record for the most runner-up finishes at one event on the ATP Tour.
^Points earned from 2019 and 2020 tournaments will be dropped depending on the best result during those periods. Only 2020 points will be dropped by 50%, including their 2020 points whichever is greater. 2019 points which are higher will still be dropped as normal.
The following players received wild cards into the main singles draw: