The blastogenic responses of lymphocytes from chemically-induced (streptozotocin) and genetically-diabetic C57B1/6J (ob/ob) obese mice were assessed using mixed-lymphocyte cultures (MLC) and mitogens selective for thymus-derived (T cell) and bone marrow-derived (B cell) lymphocytes. Splenic lymphocytes from obese and normal C57B1/6 mice exhibited similar responses to the nonspecific T and B cell mitogens, Concanavalin A (Con A) and E. coli lipopolysaccharide (LPS), respectively. A small (25%) depression of the blastogenic response in MLC was observed for lymphocytes from obese mice. The generation of cytotoxic T cells in vitro in response to trinitrobenzene sulphonic acid (TNP)-modified syngeneic spleen cells was the same for normal and obese mice. In contrast, splenic lymphocytes from 7-14 day streptozotocin-diabetic mice had lower (56-60%) proliferative responses in MLC. The generation of cytotoxic effector cells in vitro was lower for spleen cells for spleen cells from 22-day streptozotocin mice, although blastogenic responses in MLC were not depressed. The insulin-deficient streptozotocin mice appear to have a depression of some thymus-derived cell functions that may be associated with streptozotocin rather than the diabetic state. Direct immunosuppressive effects of streptozotocin are indicated by the marked decrease in the number of lymphocytes in the thymus, lymph nodes, and spleen.