The ingestion of dehydroisoandrosterone (DHA), a naturally occurring steroid, inhibits the development of autoimmunity, neoplasias, and other disorders of rodents. Potential mechanisms of action include (1) the induction of peroxisomal proliferation and (2) the conversion of DHA to androgens. We evaluated the immune system of mice fed DHA. Dietary DHA had no significant effect on antibody responses, cutaneous sensitivity reactions, natural killer activity, or graft-versus-host reactions. However, a decrease in lymphoid organ cellularity and an absence of splenic germinal centers were observed. We assessed progenitor cell activity in irradiated mice by evaluating the repopulation of marrow and lymphoid organs. Dehydroisoandrosterone feeding resulted in an inhibition of lymphopoiesis but not myelopoiesis. Clofibrate, another peroxisomal proliferator, failed to inhibit lymphocyte repopulation after irradiation. Androgen-non-responsive Tfm/Y mice were as susceptible as control mice to the inhibitory effects of DHA on lymphopoiesis. Thus DHA itself may act on lymphoid progenitor cells and/or the microenvironment.