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.
Briton Andy Murray, seeded fourth, will open proceedings on centre court against the experienced Finn Jarkko Nieminen.
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.
Frenchwoman Virginie Razzano, who knocked out pre-tournament favourite Serena Williams in the first round, will be on Court One against unheralded Dutchwoman Arantxa Rus.
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.
Jarkko Nieminen (FIN) v. Andy Murray (GBR)
Jarmila Gajdosova (AUS) v. Caroline Wozniacki (DEN)
Paul-Henri Mathieu (FRA) v. John Isner (USA)
Ayumi Morita (JPN) v. Maria Sharapova (RUS)
Urszula Radwanska (POL) v. Petra Kvitova (CZE)
Denis Istomin (UZB) v. Rafael Nadal (ESP)
Na Li (CHN) v. Stephanie Foretz Gacon (FRA)
Grigor Dimitrov (BUL) v. Richard Gasquet (FRA)
David Ferrer (ESP) v. Benoit Paire (FRA)
Francesca Schiavone (ITA) v. Tsvetana Pironkova (BUL)
Dmitry Tursunov (RUS) v. Julien Benneteau (FRA)
Virginie Razzano (FRA) v. Arantxa Rus (NED)
Maria Kirilenko (RUS) v. Klara Zakopalova (CZE)
Marcos Baghdatis (CYP) v. Nicolas Almagro (ESP)
Janko Tipsarevic (SRB) v. Jeremy Chardy (FRA)
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)
Robin Haase (NED) v. Mikhail Youzhny (RUS)
Carla Suarez Navarro (ESP) v. Sesil Karatantcheva (KAZ)
Juan Monaco (ARG) v. Lukas Rosol (CZE)
Kaia Kanepi (EST) v. Irina-Camelia Begu (ROU)
Christina McHale (USA) v. Lauren Davis (USA)
Sergiy Stakhovsky (UKR) v. Tommy Haas (GER)
Bernard Tomic (AUS) v. Santiago Giraldo (COL)
Nina Bratchikova (RUS) v. Claire Feuerstein (FRA)
Philipp Kohlschreiber (GER) v. Leonardo Mayer (ARG)
Sofia Arvidsson (SWE) v. Yaroslava Shvedova (KAZ)
Melinda Czink (HUN) v. Anastasia Pavlyuchenkova (RUS)
Florian Mayer (GER) v. Eduardo Schwank (ARG)