Group A streptococcal pyrogenic exotoxin (SPE) types A, B, and C induced lymphocyte proliferation both specifically and nonspecifically, and the responses showed characteristics associated with both types of stimulation. Guinea pig lymphocytes from animals presensitized to SPE A displayed immunologically specific proliferation in response to SPE A; control lymphocytes showed little activity in the presence of SPE A. Lymphocytes from guinea pigs not presensitized to SPE responded nonspecifically to SPE types B and C. Guinea pig lymphocytes from SPE A-presensitized animals showed enhanced proliferation over controls when treated with SPE B, suggesting that a degree of cross-reactivity between SPE types may exist, though they are serologically distinct. Mouse splenic lymphocytes exhibited low-level responsiveness to all SPE types, as would be expected for an antigen-specific proliferative response. Unlike mouse splenic lymphocytes, rabbit spleen cells and human cord blood, lymphocytes responded nonspecifically to all SPE types. Although rabbit spleen cells and human cord blood lymphocytes responded nonspecifically, the maximum response occurred at day 4 or 5, comparable to an antigen-specific system rather than a day 2 or 3 such as that with the nonspecific thymus-derived cell mitogen, concanavalin A.