Data from several clinical studies have suggested that amantadine, which has dopaminergic agonist and glutamatergic antagonist effects, may be useful for the treatment of cocaine dependence. The interaction between amantadine and smoked cocaine was examined in 10 cocaine smokers (7 men, 3 women), who participated in a 26-day inpatient study. Participants were maintained on amantadine (0 and 100 mg bid) for 5 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition, participants smoked a sample dose of cocaine base (0, 12, 25, and 50 mg) once, and were subsequently given five choice opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher ($5.00). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose varied systematically. Cocaine produced stimulant-like reinforcing, subjective, and physiological effects. Amantadine maintenance did not modify the choice to self-administer smoked cocaine. These findings, taken together with the decidedly mixed literature, suggest that amantadine (100 mg bid) will not have a role in the treatment of cocaine dependence.