We have constructed Salmonella typhimurium phoP mutants and found them to be avirulent and able to induce a protective immune response. BALB/c mice survived challenge with phoP derivatives of the highly virulent S. typhimurium strains SR-11 and SL1344 when inoculated intraperitoneally and per oral with doses equivalent to 10(4) 50% lethal doses (LD50) of the parent virulent strains. The avirulent mutants were able to establish an infection of the Peyer's patches of orally infected animals for up to 10 days after inoculation but were very inefficient at reaching the spleens. Despite the low level of infectivity of these mutants, immunized animals developed a delayed-type hypersensitivity (DTH) response to Salmonella antigens and resisted challenge with up to 10(4) LD50 of the virulent parent strain 30 days after immunization.