Treatment of mice with the direct-acting alkylating agent methyl methanesulfonate produced marked suppression of the humoral response to sheep erythrocytes and suppression of T cell responses to foreign antigens. These effects occurred without loss of spleen, thymus or body weight and in the absence of peripheral blood, splenic or bone marrow cytotoxicity. In comparison, exposure to urethan decreased spleen weight, number and viability of spleen cells, and numbers of circulating lymphocytes. Significant suppression of T cell mitogen responsiveness was observed at all dose levels of urethan. Thymus weights, proliferative responses to the B cell mitogen lipopolysaccharide and delayed hypersensitivity responses were decreased at the highest urethan dose. Cyclophosphamide treatment significantly depressed thymic weight, lymphoproliferative responses of T and B cells, antibody production and delayed hypersensitivity responses. These results suggest differential sensitivity in components of the host defense system to weak carcinogens.