Resistance to infection with Yersinia pestis was found to depend on whether the macrophage can inactivate and withstand the cytotoxic effects of phagocytized Y. pestis. Serum from mice immunized with antigens of Y. pestis enhanced the resistance of monolayers of normal cultures to the cytotoxic effects of Y. pestis and increased the capacity of peritoneal exudate cells from immune mice to inactivate these bacteria. The enhancing component of the serum was not removed by absorption with heat-killed Y. pestis. Similar enhancement was provided by supernatant fluids of spleen cultures from immunized mice but not by those from unimmunized mice. Pretreatment of spleen cells with rabbit hyperimmune antiserum to mouse brain theta-antigen plus complement caused a reduction in the enhancing capacity of the spleen cell culture fluids. Removal of the glass-adherent cell population from suspensions of primed spleen cells prior to in vitro antigenic stimulation resulted in a loss of activity from the subsequently harvested culture fluids. Thus, the enhancing component of the serum appears to be a product of thymus-derived lymphocytes (T-cells). Furthermore, splenic macrophages seem to be required for the interaction of primed T-cells with heat-killed Y. pestis.