The objective of these studies was to determine if the immunotoxic effects of cocaine in mice are sex- and strain-dependent, a profile of activity previously described for cocaine-induced hepatotoxicity. The latter effect has been attributed to differences in the metabolism of cocaine by the cytochrome P-450 system. Subchronic, (14-day) in vivo administration of cocaine to female B6C3F1 mice showed a significant decrease (80%) in the T-dependent primary antibody response only at 80 mg/kg, although exposure to 60 mg/kg produced only a 20% decrease. In contrast, exposure to 60 mg/kg cocaine in female DBA/2 mice produced a significant decrease of 50%. An even greater effect was observed in male mice where exposure to 40 mg/kg cocaine produced > 50% decreases in both B6C3F1 and DBA/2 mice. Similar results were obtained when male mice were only exposed for 7 days. Confirmation that hepatotoxicity occurred with a similar profile of sex- and strain-dependency was obtained in parallel studies when serum chemistries were measured. The immunosuppressive activity of cocaine in female B6C3F1 mice was markedly increased when mice were pretreated with phenobarbital, a cytochrome P-450 inducer. These results extend our previous studies that indicated that cocaine-induced immunosuppression occurs under conditions that are consistent with a mechanism mediated through metabolism by the cytochrome P-450 pathway.