The effects of adriamycin (AM) and its analog daunomycin (DM) on immunological responsiveness have been investigated in an effort to elucidate whether a differential interaction of the two drugs with the immune system could play a role in the higher antineoplastic activity of AM. It was found that AM induced a greater reduction in the number of antibody-producing cells after primary stimulation with sheep erythrocytes, whereas DM was more suppressive on the secondary response to the same antigen. Primary reactivity to the T-independent antigen S-III was reduced by AM, whereas DM was ineffective in the same conditions even at high doses. In addition, when a tumor allograft model was investigated, DM was significantly more immunosuppressive than was AM administered at equitoxic doses. In contrast, these agents displayed similar activity in reducing bone marrow stem cells and in inhibiting DNA synthesis in this organ. The possibility that the different immunosuppressive capacity of AM and DM contributes to the greater antitumoral activity of the former is advanced.