The protective effect of primed CD4 T cells against a lethal dose of Salmonella typhimurium was studied in Lewis rats. Primed CD4 T cells were obtained by inoculating Lewis rats with a non-lethal dose of S. typhimurium. Four weeks after the infection, spleen CD4 T cells were separated by antibody-coated magnetic microspheres using an antibody against the CD4 molecule (W3/25). The cells were separated according to their expression of the CD45RC isoform of the leukocyte common antigen by FACS. CD45RC+ and CD45RC- CD4 T-cell subpopulations were transferred to untreated rats 24 h prior to infection with S. typhimurium. Transfer of CD45RC+ and CD45RC- CD4 T cells induced a significant survival, p = 0.022 and p = 0.023 respectively, following inoculation with S. typhimurium compared to animals with no cells transferred. The infection induced an increase in CD4 T cells expressing the CD45RC isoform compared to untreated controls (p <0.001). It is concluded that both CD45RC+ and CD45RC- cells can induce a significant protection against S. typhimurium infections in rats. Therefore the CD45RC antigen cannot be used as a phenotypic marker for functionally distinct CD4 T-cell subpopulations. The infection-induced increase in CD45RC+ cells is most likely due to generation of antigen-specific memory T cells.