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Cocaine was found to inhibit in vitro mitogen-stimulated rat B and T lymphocyte proliferation in a dose-dependent manner. The IC50 for B lymphocytes (70 microM) was 2 to 4 fold lower than that obtained with T lymphocytes. To determine whether ion channel blockade or inhibition of monoamine uptake produced a similar suppression of lymphocyte proliferation, the effects of pharmacological agents sharing each of these properties with cocaine were examined. Lidocaine (0.5 mM), a sodium channel blocker, had no significant effect on B and T cell proliferation. By comparison, cocaine inhibited lymphocyte responses by greater than 80 percent at this concentration. Monoamine uptake inhibitors were also found to suppress lymphocyte proliferation in a dose-dependent manner similar to that obtained with cocaine. Of those tested, desipramine and fluoxetine were considerably more potent than cocaine, nomifensine and nisoxetine. These data demonstrated the addition of cocaine directly to lymphocyte cultures resulted in a dose-dependent inhibition of proliferation which was not due to Na+ channel blockade. Instead, the resemblance of monoamine uptake inhibitors to the action of cocaine suggests that lymphocytes may be intrinsically sensitive to these agents.