The immunomodulatory effects of adriamycin, a clinically used tumor antibiotic, were studied. A 5-day course of adriamycin therapy in mice led to a suppression of the primary but not of the secondary humoral response to sheep erythrocytes without significant alterations in peripheral blood leukocyte subsets or lymphocyte subpopulations in the spleen. The delayed type hypersensitivity (DTH) response to ovalbumin or alloantigens was not inhibited. Adriamycin-treated spleen cells were unable to stimulate an allogeneic mixed leukocyte reaction, which shows that antigen presentation is inhibited by this drug. Adriamycin-treated murine skin grafts show a prolonged survival after allotransplantation despite their unimpaired ability to induce DTH. The possible cellular mechanisms of these effects and clinical relevance of adriamycin are discussed.