In previous studies, we have shown the rapid in vitro induction of IFN gamma from human T cells by highly purified peptic extracts of M proteins from Streptococcus pyogenes. The present report extends these in vitro studies and shows that a mixture of both alpha/beta and gamma IFN were present in spleen cell homogenates after in vivo treatment with M protein wild-type (M+) or mutant (M-) S. pyogenes strains. The levels of bacterial-induced IFN were found to be greater in M+ treated animals. Additional studies in vivo showed that pretreatment of mice with heat-killed M+ S. pyogenes organisms significantly protected mice to pneumococcal infection compared to similarly treated M- or control animals (P less than 0.001). Further, antibodies to mouse IFN alpha/beta and antibodies specific to a synthetic N-terminal peptide of mouse IFN gamma enhanced the death of animals due to pneumococcal infection and blocked the protection observed in animals previously treated with heat-killed M+ organisms. Most importantly, treatment of mice with either type of IFN alone enhanced the survival of mice to levels similar to that observed by treatment with M+ organisms (P less than 0.05). The results strongly suggest that IFN can play a crucial role, directly or indirectly, in controlling infection by Streptococcus pneumoniae and perhaps other streptococci.