Cytolytic T lymphocytes (CTLs) are generally thought to recognize cellular antigens presented by class I MHC molecules. A number of studies, however, have revealed responses of considerable magni-tude involving both CD8⁺ and CD4⁺ CTLs with class II restric-tion^1–5, suggesting that class Il-restricted CTLs recognizing exogeneous protein antigens may exist. As class II antigens are normally expressed on limited types of cells such as B cells and macrophages, such CTLs might be expected to exert a suppressive effect on antibody responses. Here we report that stimulation of mouse lymphocytes with a soluble antigen induced CD8⁺ and CD4⁺ CTLs specific for the antigen with class II restriction. The specific lysis was far more efficient when target B cells specifically recognized the antigen than when they did not, indicating that the primary targets for these CTLs are probably B cells expressing immunoglobulin receptors reactive for the same antigen molecule. These results suggest that the natural occurrence of such CTLs during immune responses may explain antigen-specific suppression on antibody responses by T cells.