Three-time champion Serena Williams could face longtime rival Maria Sharapova in the French Open last-16 after Thursday's draw which also handed Rafael Nadal a dream route to an 11th title.
Serena, the champion in 2002, 2013 and 2015, will start against Kristyna Pliskova of the Czech Republic.
Former world number one Williams, now ranked a lowly 453, is playing a Grand Slam for the first time since she won her 23rd major at the 2017 Australian Open after which she stepped off the tour to give birth to her daughter in September.
Pliskova, the twin sister of world number six Karolina, has never won a main draw match at Roland Garros.
Williams, 36, has played just four matches on the tour in 2018 and not featured at all since Miami in March.
Sharapova, champion in 2012 and 2014, could face Serena, against who she lost in the 2013 final at Roland Garros, in the fourth round.
The Russian, who missed last year's event after she was refused a wild card as she battled to rebuild her career following a 15-month doping ban, has not defeated Williams since 2004.
The American leads their head-to-head series 19-2.
Top seed and two-time runner-up Simona Halep faces Alison Riske of the United States in her opener while second seed and Australian Open champion Caroline Wozniacki starts against another American, Danielle Collins.
Top seed Nadal starts his bid for an 11th Roland Garros title against Ukraine's world number 54 Alexander Dolgopolov.
Nadal, fresh from an eighth Rome clay court title having also won his 11th trophies in Barcelona and Monte Carlo already this spring, has a 7-2 record over Dolgopolov.
"It's always special when I come back to Paris where I have had so many wonderful moments in my career," said Nadal at the draw ceremony ahead of the French Open which starts on Sunday.
One glance at the draw would have left the 31-year-old Spaniard feeling even more special after former champions Novak Djokovic, Stan Wawrinka as well as clay court dangerman Dominic Thiem all landed in the other half of the draw where Alexander Zverev is the second seed.
Nadal's path to the final could see him face childhood friend Richard Gasquet in the third round, possibly Denis Shapovalov in the last-16, then Kevin Anderson, who he beat in the 2017 US Open final, and third-seed Marin Cilic in the semi-finals.
Zverev, who lost to Nadal in the Rome final last weekend, has never got beyond the third round in Paris and was defeated in the first round last year.
The 21-year-old German, who is seeded second in the absence of Roger Federer, begins his French Open against Ricardis Berankis of Lithuania.
Djokovic, the 2016 champion, starts against a qualifier and could meet Grigor Dimitrov in the fourth round.