While fourth seed Nadal, playing one of his best Roland Garros, is expected to overwhelm his compatriot on Court Philippe Chatrier, defending champion Novak Djokovic can expect tougher opposition against Austrian Dominic Thiem, the sixth seed.
Both matches were rescheduled after rain disrupted Tuesday's programme. No rain is expected on Wednesday although the wind could be a factor.
World number one Andy Murray, who has been improving since arriving in Paris, takes on Japanese eighth seed Kei Nishikori, who was handed his first grand-slam bagel in six years in the third round.
Former champion Stan Wawrinka will be the clear favourite when he takes on Marin Cilic as the top four looks set for a semi-final reunion.
The women's draw is side open and Caroline Garcia will hope to become the first French woman to reach the semi-finals since Marion Bartoli in 2011 when she faces world number three Karolina Pliskova.
In a match dubbed 'the final before the final', Romanian Simona Halep plays Ukraine's Elina Svitolina.
(Reporting by Julien Pretot; Editing by Amlan Chakraborty)
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