Between them they won the four main leadup events on the surface at Charleston and Madrid for the American and at Stuttgart and Rome for the Russian.
The question is whether one of them can sustain their form through two weeks and seven matches in the often unpredictable playing conditions that are a mark at the famed Roland Garros complex on the western edge of Paris.
Williams, whose only win here came 10 years ago when she defeated sister Venus in the final, has staged yet another impressive return to form in recent weeks.
The 30-year-old defeated Lucie Safarova in the final at Charleston before pounding world number one Victoria Azarenka 6-1, 6-3 to take the Madrid Open title at the start of May.
She subsequently withdrew from the semi-finals of last week's Italian Open with a lower back injury but has expressed confidence she will be fully fit to challenge for the title in Paris.
"I'm feeling better on clay than I did at the US Open (where she lost in the final to Samantha Stosur). I have a better ranking and my fitness is better," the 13-time Grand Slam champion said..
"I just feel better this time around. I feel I can play on any surface and that's the right attitude for me. I'm enjoying my tennis. This is where I belong and what I do best."
Sharapova, at 25, is a late convert to claycourt tennis having once described her movement on the slippy red dirt surface as being "like a cow on ice".
She reached the semi-finals last year before losing to eventual champion Li Na and it was the Chinese player she defeated last weekend to defend her Italian Open crown in Rome.
She also chalked up a straight sets win over Azarenka in the final at Stuttgart, a win that followed losses to the Belarussian in the finals at the Australian Open and Indian Wells.
But her only encounter so far this year with Serena Williams resulted in a 6-1, 6-3 thumping in the quarter finals in Madrid.
There is also the question of whether Sharapova's notoriously inconsistent serve can survive through two weeks of outdoor conditions with gusts of wind whipping up the dirt particles and causing all sorts of havoc.
The Russian though is quietly confident that she has a realistic chance of completing her career haul of Grand Slam titles having previously won Wimbledon and the US and Australian Opens once apiece.
Of her play on clay she said: "I have improved and most of it comes down to the physical aspect and patience and not changing my game but relying on the things I have improved like sliding and playing and definitely on the serve and this is helping."
Defending champion Li, who last year made history in Paris by becoming the first Asian player to win a Grand Slam singles title, showed in her run to the Rome final, where she stretched Sharapova to a third set tie-breaker, that she is running into form at just the right time and could challenge again.
Azarenka, however, seems to have stalled after a tremendous start to the year that saw her win four tournaments, including the Australian Open, and rise to number one in the world rankings for the first time.
She will be the top seed in Paris but there are injury doubts following her withdrawal from her third round match in Rome with a shoulder injury. She has also has been troubled by a wrist injury.
The east European challenge could also come from Wimbledon champion Petra Kvitova of the Czech Republic and the consistent, but lightweight, Agnieszka Radwanska of Poland, while US Open champion Samantha Stosur of Australia and 2010 French Open winner Francesca Schiavone of Italy both have the games to go deep at Roland Garros.
The joker in the pack could be Dane Caroline Wozniacki who has tumbled from the world number one position she held last year and is currently at ninth, but is still capable of a return to top form.
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