Rome will be Williams's fourth tournament of the season and the first since being forced to withdraw from the Miami Open in April due to a knee injury.
The 37-year-old American -- now ranked 11th -- has completed just seven matches this year, also withdrawing from Indian Wells in March with illness.
There are now doubts that the veteran can add to her tally of 23 Grand Slams, something which has so far proved beyond her since returning last year after taking time out following the birth of her first child.
Her last Grand Slam singles title was won at the Australian Open in 2017, where she was pregnant, breaking a tie with Steffi Graf for the most in the professional era.
Her win in Melbourne moved her one behind Australian Court's record of 24 major singles titles.
After giving birth to her daughter Olimpia in September 2017, Serena made her return to Grand Slam tennis at last year's French Open, where she reached the fourth round.
She reached the finals of Wimbledon and the US Open, suffering a meltdown in Flushing Meadows, as she smashed her racquet and called the umpire a "thief" and a "liar" in a temper tantrum after losing to Naomi Osaka.
More drama followed in the quarter-finals of this year's Australian Open, when she suffered a spectacular collapse in a three-sets defeat by Karolina Pliskova.
Williams led 5-1 in the decider before failing to convert four match points and losing six games in a row.
She has admitted that it has been tougher than expected to get back winning after her maternity leave.
"From day one, I expect to go out and, quite frankly, to win. That hasn't happened. But I do like my attitude," she said.
"I like that I don't want to go out there and say: 'I expect to lose because I had a year off. I've been playing for 10 months. I'm not supposed to win.' I don't have that attitude."
Rome is a special place for Williams who met her husband Alexis Ohanian in the Eternal City in May 2015, a year when she withdrew from the tournament with an elbow injury.
A four-time Rome winner Williams last won at the Foro Italico in 2016 defeating her compatriot Madison Keys in a straight-set final.
She also won the Rome title in 2002, 2013 and 2014.
This year she is in the top half of the draw along with world number one Naomi Osaka, Kiki Bertens, and Simona Halep.
Three of the four semi-finalists from Madrid are in the top half, along with winner Kiki Bertens and runner-up Simona Halep.
Williams will open against a qualifier and could face older sister Venus Williams in the second round.
Should Serena and Venus meet in Rome, it will be their first meeting on European clay in nearly 17 years.
Their last meeting on red clay came at the 2002 Roland Garros final.
Two-time defending champion Elina Svitolina comes in short on form after a knee injury but could have an opportunity as she plays in the bottom half of the draw.
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