Over the past several years there has been a steady increase in the incidence of immunologically compromised patients. This has been the result of both chemical agents, such as those used in cancer chemotherapy, and biological agents such as HIV, the cause of Acquired lmmunodefeciency Syndrome (AIDS). The increase in immune-suppressed patients has lead to an increase in life-threatening mycoses requiring treatment with antifungal agents. Pharmaceutical companies have increased research for the development of new antifungal agents which are more effective and less toxic than those that are currently used. Several researchers have reported on antifungal agents that demonstrate both positive and negative effects on the immune system. Because antifungal therapy relies on host immune defenses in eliminating diseases, more emphasis is being placed on how antifungal agents interact with the immune system. The purpose of this study was to evaluate the effects of Ketoconazole, ltraconazole and Fluconazole on T- and B-cell proliferation and natural killer cell activity using normal, cyclosporine-compromised and cyclophosphamide-compromised immune models in mice. T and B cells obtained from the spleens Balb/c mice were mitogen stimulated and grown in the presence of 0, 1, 2, 4, 8 and 16 µg/ml of these 3 antifungal agents. Cell proliferation was determined by the uptake of 3[H]-thymidine and was measured as counts per minute. Natural killer cell activity was measured by the release of 51-sodium chromate (51Cr) into the supernatant by 51Cr-labeled Yac cells. Ketoconazole caused a significant reduction in cell proliferation in all immune models in both T and B cells. Itraconazole also significantly inhibited cell proliferation in all models in both T and B cells as well as natural killer (NK) cell activity in the immune-normal model. Viability studies on mitogen-stimulated lymphocytes suggest that inhibitory effects of Katoconazole and Itraconazole on lymphocyte proliferation are due to toxic effects. Fluconazole appears to have few if any inhibitory effects on either cell proliferation or natural killer cell activity.