In the present study, we investigated the effect of intravenously (i.v.) administered cocaine on mitogen-induced lymphocyte proliferation and NK cytolytic activity in rats implanted with indwelling jugular cannula. To assess whether the effects of cocaine were accompanied by adrenal gland activation, plasma corticosterone concentrations were also determined. It was found that the i.v. infusion of cocaine resulted in both a time- and dose-dependent decrease in both blood and splenic Con-A-stimulated lymphocyte proliferative responses. Within 60 minutes, blood responses were maximally inhibited by more than 60% with 5 mg/kg cocaine. By 4 h, the suppression of blood lymphocyte responses was no longer significant. In contrast to these findings, there were no significant effects observed with splenic lymphocyte responses until 4 h after drug administration. At this time, cocaine at doses of 5 and 10 mg/kg inhibited splenic proliferative responses by 50 and 75%, respectively. These effects appeared to be selective, since no concurrent decreases in NK cell activity were observed with 5 mg/kg at either 2 or 4 h. Within 30 min, plasma corticosterone concentrations were maximally increased by 10-fold with 5 and 10 mg/kg doses of cocaine. At lower doses of cocaine (1 mg/kg), neither changes in lymphocyte proliferative responses, NK cytolytic activity nor plasma corticosterone levels were apparent. This study demonstrates that a single i.v. infusion of cocaine results in a selective dose- and time-dependent immunosuppression which is preceded by transient increases in circulating levels of corticosterone.