The genotype of a mouse influences whether or not it will survive infection with the agent of murine typhoid, Salmonella typhimurium. The best-characterized murine salmonella response gene is a Chromosome 1 locus designated Ity. Inbred strains of mice that express the Itys allele are unable to contain the net growth of Salmonella typhimurium within their spleens and livers, and usually die early in the infection. By contrast, mice homozygous or heterozygous for the Ityr allele are able to control the net multiplication of Salmonella typhimurium within these organs. The Ity gene also appears to regulate the extent of replication within murine reticuloendothelial cell tissues of the obligate intracellular parasite Leishmania donovani, as well as the facultative intracellular bacteria Mycobacterium bovis and Mycobacterium lepraemurium. Previous studies from our laboratory strongly suggested that Ityr mice are more resistant to S. typhimurium infection than are Itys mice, because resident Ityr macrophages kill salmonellae more efficiently than do Itys macrophages. In this study, we used an in vitro macrophage assay to assess the specificity of the enhanced killing capacity of Ityr macrophages. We found that Ityr macrophages were better able than Itys macrophages to kill both intracellular bacteria (Salmonella typhi) and extracellular bacteria (Escherichia coli, Staphylococcus aureus, Corynebacterium diphtheriae). Thus, the diversity of organisms affected by Ity expression suggests that the product of this gene may play a key regulatory role in the initial interaction of mice with a variety of microbial agents.