Ifenprodil is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist which prefers NR2B-containing NMDA receptors to NR2A-containing NMDA receptors. It has been reported that ifenprodil suppresses morphine-induced place preference in mice. In this study, the effects of ifenprodil on the discriminative stimulus effects of cocaine were examined in rhesus monkeys. Five monkeys were trained to discriminate cocaine at 0.25 or 0.5 mg/kg im from saline using a standard two-lever drug-discrimination paradigm under a fixed-ratio schedule of food reinforcement. A single dose of cocaine (0.06-0.5 mg/kg) produced a dose-dependent increase in cocaine-appropriate response, and training doses produced 100% cocaine-lever response in each monkey. Pretreatment with ifenprodil (1 or 2 mg/kg, i.v.) blocked the cocaine-appropriate response when low doses of cocaine were used. The results suggest that NR2B-containing NMDA receptor-mediated mechanisms modulate the discriminative stimulus effects of cocaine in rhesus monkeys.