Studies concerned with the mechanisms responsible for relative resistance or susceptibility of strains of inbred mice to Trypanosoma musculi infections are presented. Treatment with 400 rads of ionizing radiation, silica dust, or trypan blue (reticuloendothelial blocking agents) rendered C3H mice unable to control the initial maximum level of parasite growth, and the mice died of overwhelming infections. In contrast, similarly treated C57BL/6 (relatively resistant) mice controlled initial trypanosome growth as well as controls; however, the duration of infection, preceding eventual cure, was approximately doubled. Combined treatment with trypan blue and 400 rads of radiation resulted in much higher initial levels of infection in C57BL/6 mice, and about half of the mice died; the remaining mice eventually recovered after a prolonged course of infection. These results indicate that a nonimmunological mechanism, which controls initial infection, and an immunological mechanism cooperate to limit T. musculi infections in normal mice. We present results that suggest that both mechanisms are less effective in C3H than in C57BL/6 mice. The initial control of infection presumably reflects the activity of some type(s) of phagocytic effector cell; we show, however, that the initial control of infection is not an attribute of the liver Kupffer cells. Identification and characterization of the cells capable of controlling initial infection could lead to procedures for enhancing their function and, thus, to enhanced resistance to, and elimination of, trypanosome infections.