Resolution of infection with attenuated Salmonella is an active process that requires CD4⁺ T cells. Here, we demonstrate that costimulation via the surface molecule CD28, but not antibody production by B cells, is required for clearance of attenuatedaroA Salmonella enterica serovar typhimurium. In contrast, specific antibody is critical for vaccine-induced protection against virulent bacteria. Therefore, CD28⁺CD4⁺ T cells are sufficient for clearance of avirulentSalmonella in naive hosts, whereas CD4⁺ T cells and specific antibodies are required for protection from virulentSalmonella in immune hosts.