Specific pathogen-free ICR (Institute of Cancer Research) mice were challenged with Salmonella orally, aerogenically, or parentally 24 hr after they received sublethal whole-body irradiation. The early growth for the sublethal inoculum was identical in irradiated and control mice. In the irradiated group, Salmonella multiplied in the liver and spleen until death of the host. Increasing the dose of irradiation reduced the size of the mean lethal dose for the intravenous, intraperitoneal, and aerogenic challenges. However, in the orally challenged mice, the 50% lethal dose dropped only 100-fold when the radiation was increased from 0 to 400 rad, with little further decrease even when the dose was increased to 800 rad. Presumably, the local gut defenses were responsible for this considerable disparity in the lethal effects of an oral vs. parenteral challenge. No evidence was found for enhanced local infection of the gut or increased involvement of the gut-associated lymphoid organs in the irradiated host. The increased mortality seen in the irradiated group seemed to be associated with a continued unrestricted growth of Salmonella in the liver and spleen when the number of peripheral blood leukocytes was at a minimum. Resistance to the sublethal salmonella challenge was eventually restored as the total counts of white blood cells returned to normal.