It will be the 22nd career match-up between the two long-time rivals, who somehow have avoided each other at the US Open throughout their long careers.

Twelve months after losing the final to Naomi Osaka, Williams will have to hit the ground running in her quest for a 24th Grand Slam title.

But the 37-year-old American will take confidence from her dominant 19-2 head-to-head record against five-times Grand Slam winner Sharapova, who is unseeded.

Williams has won the US Open six times, while Sharapova's lone title was in 2006.

Sharapova beat Williams twice in 2004, but has not prevailed since, not counting a walkover in the 2018 French Open, where the American pulled out with an injury.

If Williams, the eighth seed, beats Sharapova and subsequent opponents, she could meet top seed Osaka again in the final, as the pair are on opposite sides of the draw.

Last year's final ended in acrimony between Williams and chair umpire Carlos Ramos, after he gave her three code violations in the second set.

Williams has not played since retiring with a back injury in the final of the Rogers Cup in Toronto on Aug. 11.

Sharapova, ranked 87th in the world, has also battled injuries this year and was beaten by Ash Barty in the second round of the Cincinnati Masters last week.