Pre-clinical research implicates dopaminergic neurotransmission as critical in producing the effects of stimulants. Previous stimulant challenge studies using volunteers treated with dopaminergic antagonists have generally failed to demonstrate reduction of subjective effects. We performed this study to determine whether repeated dosing with risperidone reduced the subjective effects of experimentally administered cocaine. Nine non-treatment seeking hospitalized cocaine-dependent volunteers received 40 mg cocaine IV before and following 5 days of treatment with risperidone, 2 mg per day. Risperidone pre-treatment reduced the self-rated 'high' produced by cocaine. Repeated, rather than single, dosing with a D2 antagonist may be necessary to reduce the subjective effects produced by cocaine. The degree of D2 receptor blockade produced by risperidone appears to be greater than the reduction in euphoric effects produced by cocaine, suggesting that mechanisms other than those involving D2 receptors may be important in drug-induced euphoria.