Inbred mice infected intraperitoneally (ip) with Salmonella typhimurium showed three patterns of survival: susceptible (C57Bl/6J, BALB/cJ, and C3H/HeJ strains), intermediate (DBA/2J strain), and resistant (A/J strain). Vaccination with phenol-killed bacteria, live avirulent S. typhimurium, or ribosomal vaccine protected strain A/J but not other strains against ip infection. Normal F1 hybrid mice were not more resistant to ip infection than either parent, but vaccination of hybrids with phenol-killed bacteria elicited equal or greater resistance than that of either vaccinated parent. Strain A/J infected by the intragastric or intravenous route was also more resistant than strain C57Bl/6J. Live avirulent S. yphimurium protected A/J but not C57Bl/6J mice against iv infection with the virulent strain. A/J mice were susceptible to Listeria monocytogenes and Cryptococcus neoformans; C57Bl/ 6J mice were resistant. C57Bl/ 6J mice may be unable to activate tissue macrophages in S. typhimurium infection, while vaccination prolongs survival of A/J mice until cellular immune mechanisms can mount an effective defense.