Staphylococcal pyrogenic exotoxin type C (PE-C) suppressed synthesis of IgM antibodies to sheep erythrocytes by in vitro cultures of murine and rabbit splenocytes. Maximal suppression was observed on day 4 of culture and at PE-C doses of 0.1 and 0.01 microgram per 10(7) splenocytes. Endotoxin, added to cell cultures containing PE-C, caused further suppression of IgM synthesis. Endotoxin alone added to cultures was not immunosuppressive. Sublethal doses of PE-C plus endotoxin also suppressed complement-fixing antibody responses in rabbits to sheep erythrocytes; neither agent alone was suppressive. Further, the combination of PE-C and endotoxin blocked reticuloendothelial clearance of colloidal carbon by 50% during a 20-min period. PE-C enhanced the skin reactivity of rabbits previously sensitized to purified protein derivative. One-half of rabbits immunized with PE-C emulsified in adjuvant failed to make antibody to PE-C during a 112-day period. The animals that were nonresponsive to PE-C were able to make antibodies to sheep erythrocytes.