Serena Williams' 1,000th tour-level match ended in defeat as she marked her return to action with a 7-6 (6), 7-5 loss to Nadia Podoroska on Wednesday in the second round of the Italian Open.

The eighth-seeded Williams, who hadn't played since the Australian Open, came from a break down twice in the opening set and saved the first three set points she faced in the tiebreaker before Podoroska converted her fourth. The Argentine went on to win in 1 hour, 58 minutes.

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Serena Williams of the United States shouts during her match against Nadia Podoroska of Argentina at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. Podoroska beat Williams 7-6, 7-5. (AP PhotoAlessandra Tarantino)

Serena Williams' 1,000th tour-level match ended in defeat as she marked her return to action with a 7-6 (6), 7-5 loss to Nadia Podoroska on Wednesday in the second round of the Italian Open.

Serena Williams of the United States, left, and Nadia Podoroska of Argentina greet each other at the end of their match, at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. Podoroska beat Williams 7-6, 7-5.(AP PhotoAlessandra Tarantino)

The 24-year-old Podoroska took a 5-2 lead in the second set but was broken at love the first time she tried to serve out the match. However, she broke Williams again in the 12th game to seal her third career win over a top-10 player.

Nadia Podoroska of Argentina celebrates at the end of her match against Serena Williams of the United States, at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. Podoroska beat Williams 7-6, 7-5.(AP PhotoAlessandra Tarantino)

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Serena Williams of the United States returns the ball to Nadia Podoroska of Argentina during their match at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. (AP PhotoAlessandra Tarantino)

Serena Williams of the United States returns the ball to Nadia Podoroska of Argentina during their match at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. (AP PhotoAlessandra Tarantino)

Serena Williams of the United States serves the ball to Nadia Podoroska of Argentina during their match at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. (AP PhotoAlessandra Tarantino)

Serena Williams of the United States serves the ball to Nadia Podoroska of Argentina during their match at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. (AP PhotoAlessandra Tarantino)

Nadia Podoroska of Argentina returns the ball to Serena Williams of the United States during their match at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. (AP PhotoAlessandra Tarantino)

Nadia Podoroska of Argentina returns the ball to Serena Williams of the United States during their match at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. (AP PhotoAlessandra Tarantino)

“It’s tough to have a first match on clay. It was definitely kind of good to go the distance and to try to be out there, but clearly I can do legions better,” said Williams, who has won the Italian Open four times. "Maybe I do need a few more matches, so I’m going to try to figure that out with my coach and my team and see what we would like to do. ... I have been training for months, but it feels definitely different on clay to make that last adjustment.”

Serena Williams of the United States shouts during her match against Nadia Podoroska of Argentina at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. Podoroska beat Williams 7-6, 7-5. (AP PhotoAlessandra Tarantino)

Serena Williams of the United States shouts during her match against Nadia Podoroska of Argentina at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. Podoroska beat Williams 7-6, 7-5. (AP PhotoAlessandra Tarantino)

The 24-year-old Podoroska took a 5-2 lead in the second set but was broken at love the first time she tried to serve out the match. However, she broke Williams again in the 12th game to seal her third career win over a top-10 player.

In the men's tournament, Rafael Nadal was playing local teenager Jannik Sinner.

Earlier, third-seeded Daniil Medvedev lost 6-2, 6-4 to fellow Russian Aslan Karatsev.

Serena Williams of the United States, left, and Nadia Podoroska of Argentina greet each other at the end of their match, at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. Podoroska beat Williams 7-6, 7-5.(AP PhotoAlessandra Tarantino)

Serena Williams of the United States, left, and Nadia Podoroska of Argentina greet each other at the end of their match, at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. Podoroska beat Williams 7-6, 7-5.(AP PhotoAlessandra Tarantino)

More AP Tennis: https://apnews.com/hub/tennis and https://twitter.com/AP_Sports

Nadia Podoroska of Argentina celebrates at the end of her match against Serena Williams of the United States, at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. Podoroska beat Williams 7-6, 7-5.(AP PhotoAlessandra Tarantino)

Nadia Podoroska of Argentina celebrates at the end of her match against Serena Williams of the United States, at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. Podoroska beat Williams 7-6, 7-5.(AP PhotoAlessandra Tarantino)

Serena Williams of the United States returns the ball to Nadia Podoroska of Argentina during their match at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. (AP PhotoAlessandra Tarantino)

Serena Williams of the United States returns the ball to Nadia Podoroska of Argentina during their match at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. (AP PhotoAlessandra Tarantino)

Serena Williams of the United States serves the ball to Nadia Podoroska of Argentina during their match at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. (AP PhotoAlessandra Tarantino)

Serena Williams of the United States serves the ball to Nadia Podoroska of Argentina during their match at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. (AP PhotoAlessandra Tarantino)

Nadia Podoroska of Argentina returns the ball to Serena Williams of the United States during their match at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. (AP PhotoAlessandra Tarantino)

Nadia Podoroska of Argentina returns the ball to Serena Williams of the United States during their match at the Italian Open tennis tournament, in Rome, Wednesday, May 12, 2021. (AP PhotoAlessandra Tarantino)