Nadal, who last year beat Bjorn Borg's record of six Roland Garros crowns, has lost only one match on the Paris clay and has already won five titles on the slow surface this year.
However, Serbia's Djokovic ended the Spaniard's eight-year reign at the Monte Carlo Masters to show he is beatable on the red dust after all.
Cold and wet weather could also threaten Nadal, whose devastating top spin works best on dry courts.
Temperatures are set to barely reach 15 degrees Celsius in the first week of the French Open, with rain showers forecast every day from Tuesday onwards, conditions reminiscent of 2009 when the Spaniard lost to Robin Soderling in the fourth round.
"The only negative thing is this cold," Nadal, who came back this year from a seven-month knee injury layoff, told a news conference on Friday.
Nadal, with 11 grand slam titles on all surfaces to his name, is just happy to be back playing and winning at Roland Garros again this year is not the be-all and end-all.
"If you can ask me if I win one grand slam during the whole year or win six tournaments like I already did, I will choose to win six tournaments," said the third seed, who first meets Germany's Daniel Brands.
World number one Djokovic, in contrast, has put a lot of pressure on his shoulders having yet to triumph at the French Open.
He has asked his support team and reporters not to tell him who his potential second or third round opponents are so he can focus on his opener against Belgian David Goffin.
Djokovic, who lost early in Rome and Madrid, could meet Nadal in the semi-finals of a tournament deprived of world number two Andy Murray, who pulled out because of back problems.
"This is the tournament that is the number one priority of my year, of my season. This is where I want to win and I'm going to go for it," Djokovic, who beat Nadal in the Monte Carlo final, told a news conference.
Jo-Wilfried Tsonga and Richard Gasquet, seeded sixth and seventh respectively, will be out to end France's 30-year drought for a men's grand slam champion.
The last Frenchman to win a major tournament was Yannick Noah, who beat Swede Mats Wilander in the final at Roland Garros in 1983.
In Tsonga's way stands second seed Roger Federer, who has a smooth-looking draw until a potential quarter-final clash with his sometime nemesis.
World number one Serena Williams is the top favourite in the women's draw although defending champion Maria Sharapova of Russia is also a natural candidate for a second Roland Garros title.
Once a self-described "cow on ice" on clay, Sharapova now feels at home on the slowest surface.
"It never came easy for me to play on the clay and that's why it took many years. But yet I felt like with every year I was getting closer," she told a news conference.
Eleven years after winning her only French Open, Serena is also feeling sharp as she bids for a 16th grand slam singles title.
"Just looking back at a few of my matches years ago and looking now, I definitely feel like I'm getting into that zone that I have always wanted to be in and I feel a lot better about it," the American said.
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