Robust Ab and CD4 T cell responses are required for the resolution of Salmonella infection in susceptible mice. In this study, we examined the role of B7-H1 (programmed cell death ligand 1) in resistance to primary Salmonella infection. Infected B7-H1–deficient mice had significantly higher bacterial burdens at day 21 and day 35 postinfection compared with wild-type mice, demonstrating that B7-H1 plays an important role in immunity to Salmonella. B7-H1–deficient and wild-type mice both generated Salmonella-specific IgM and IgG2c Ab responses to infection, and clonal expansion of endogenous and adoptively transferred Salmonella-specific CD4 T cells was similar in both groups. However, although Salmonella-specific IFN-–producing Th1 CD4 T cells were generated in Salmonella-infected B7-H1–deficient mice, these cells did not expand to the level observed in wild-type mice. Furthermore, fewer multifunctional Th1 cells that simultaneously secreted IFN-, TNF-, and IL-2 were detected in Salmonella-infected B7-H1–deficient mice. Together, these data demonstrate that B7-H1 is required for the generation of multifunctional Th1 responses and optimal protective immunity to primary Salmonella infection.