BALB/c mice are extremely susceptible to salmonella infections. Previous reports have suggested that this natural susceptibility is due to a defect in cell-mediated immunity (CMI) which correlates with their inability to develop a delayed (footpad) hypersensitivity reaction to a salmonella extract when immunized with attenuated salmonellae. We have shown that mice thus immunized are in fact highly resistant to superinfecting intravenous challenge with virulent organisms, at a time when the footpad test is still negative. The footpad test becomes positive 2-3 weeks later, after the appearance of CMI, which is already present at 1 week as measured by determining the fate of a superinfecting challenge in the RES. The positive footpad reactions that develop in BALB/c mice--and also in B10, and CBA and (B10XA/J)F1 mice--are transferable to normal recipients by thetasensitive spleen cells. However, although B10 mice give positive delayed hypersensitivity (DH) reactions, they are more susceptible to salmonellae of intermediate virulence than the DH negative BALB/c strain. We have also shown that previous reports which suggested that susceptible mice did not develop immunity when vaccinated with live organisms are probably due to the salmonella strain used for vaccination, which does not establish a carrier state. A strain which does establish a carrier state effectively immunizes the susceptible BALB/c strain against virulent challenge, indicating that natural susceptibility does not preclude the development of acquired immunity to reinfection. X