Normal mice and mice displaying delayed hypersensitivity to Staphylococcus aureus were challenged with a lethal dose of Listeria monocytogenes. Nonspecific antimicrobial activity was assessed by inhibition of bacterial growth in the spleen and by increased survival rates. Administration of specific staphylococcal antigen prior to challenge was a prerequisite for the induction of nonspecific resistance. Both the time of administering eliciting antigen and the route were important consideration for evoking the response. Similar responses were seen in 3 strains of inbred mice following immunization with both encapsulated and nonencapsulated staphylococci. Although enhanced resistance as measured by viable counts in the spleens was achieved after 2 injections, protection as measured by survival required 4 injections of S. aureus followed by elicitation with staphylococcal antigens. Nonspecific resistance could be detected as late as 9 weeks after the disappearance of delayed hypersensitivity.