Nadal, who has lost only once on the Paris clay since his debut in 2005, will eclipse the record of six titles he shares with Bjorn Borg if he triumphs again this year but the second-seeded Spaniard is adamant he is not obsessed with the landmark.
"We are in the second round. That's the thing. I have enough work to do thinking about the next round, and not think about if Bjorn will be here or if I'm gonna play the final," Nadal, who is scheduled second on Court Suzanne Lenglen, told reporters.
Nadal has beaten Istomin in both of their previous meetings.
Russian second seed Maria Sharapova continues her quest for a maiden title at the French Open, the only grand slam missing from her collection, against Japanese Ayumi Morita on Court Philippe Chatrier.
Also in action is Wimbledon champion Petra Kvitova of the Czech Republic, with the fourth seed starting the day on Court Suzanne Lenglen against Pole Urszula Radwanska.
Fifth seed Jo-Wilfried Tsonga of France will be on Court Suzanne Lenglen to finish his match against German Cedric Marcel Stebe after it held over due to rain. The duo will resume the third set at 1-1 having split the first two sets.
ORDER OF PLAY
Court Philippe Chatrier:
Jarkko Nieminen (FIN) v. Andy Murray (GBR)
Jarmila Gajdosova (AUS) v. Caroline Wozniacki (DEN)
Ayumi Morita (JPN) v. Maria Sharapova (RUS)
Court Suzanne Lenglen:
Urszula Radwanska (POL) v. Petra Kvitova (CZE)
Denis Istomin (UZB) v. Rafael Nadal (ESP)
Na Li (CHN) v. Stephanie Foretz Gacon (FRA)
Virginie Razzano (FRA) v. Arantxa Rus (NED)
Maria Kirilenko (RUS) v. Klara Zakopalova (CZE)
Heather Watson (GBR) v. Julia Goerges (GER)
Jesse Levine (USA) v. Milos Raonic (CAN)
Varvara Lepchenko (USA) v. Jelena Jankovic (SRB)
Marcel Granollers (ESP) v. Malek Jaziri (TUN)
Shuai Peng (CHN) v. Lourdes Dominguez Lino (ESP)
Carla Suarez Navarro (ESP) v. Sesil Karatantcheva (KAZ)
Juan Monaco (ARG) v. Lukas Rosol (CZE)
Christina McHale (USA) v. Lauren Davis (USA)
Sergiy Stakhovsky (UKR) v. Tommy Haas (GER)
Nina Bratchikova (RUS) v. Claire Feuerstein (FRA)
Florian Mayer (GER) v. Eduardo Schwank (ARG)
Play starts at 10:00 UK time