The effect of clotrimazole, an imidazole derivative with anti-rheumatic properties, on lymphocyte stimulation by phytohaemagglutinin, concanavalin-A and pokeweed mitogen was investigated in an in vitro culture system. Evidence was obtained to show that the drug could either enhance or inhibit lymphocyte stimulation, the response depending on the concentration of the drug in the culture system and the mitogen used, as well as on individual variability. At a concentration of the drug corresponding to therapeutic serum levels, clotrimazole inhibited lymphocyte response to the three mitogens in all the normal volunteers studied. In addition, the effect of clotrimazole on in vitro mitogenic responsiveness of lymphocytes of a group of patients with rheumatoid arthritis taking this drug was compared to that of the proprionic acid derivative, ketoprofen. Patients taking clotrimazole showed a significant reduction in lymphocyte responsiveness, when compared to pre- and post-treatment levels, whereas there was no significant difference in those patients taking ketoprofen. Although cortisol levels tended to be higher in the groups of patients taking clotrimazole there was no correlation between lymphocyte responsiveness and cortisol concentration.