Circulating IgM present in the body prior to any apparent Ag exposure is referred to as natural IgM. Natural IgM provides protective immunity against a variety of pathogens.Salmonella entericaserovar Typhi (S.Typhi) is the causative agent of typhoid fever in humans. Because mice are not permissive toS.Typhi infection, we employed a murine model of typhoid usingS. entericaserovar Typhimurium expressing the Vi polysaccharide (ViPS) ofS.Typhi (S.Typhimurium strain Typhi RC60) to evaluate the role of natural IgM in pathogenesis. We found that natural mouse IgM binds toS.andS.Typhimurium. The severity ofS.Typhimurium infection in mice is dependent on presence of the natural resistance-associated macrophage protein 1 (Nramp1) allele; therefore, we infected mice deficient in secreted form of IgM (sIgM) on either aNramp1-resistant (129S) or -susceptible (C57BL/6J) background. We found that the lack of natural IgM results in a significantly increased susceptibility and an exaggerated liver pathology regardless of the route of infection or theNramp1allele. Reconstitution of sIgM−/−mice with normal mouse serum or purified polyclonal IgM restored the resistance to that of sIgM+/+mice. Furthermore, immunization of sIgM−/−mice with heat-killedS.Typhi induced a significantly reduced anti-ViPS IgG and complement-dependent bactericidal activity againstS.Typhi in vitro, compared with that of sIgM+/+mice. These findings indicate that natural IgM is an important factor in reducing the typhoid severity and inducing an optimal anti-ViPS IgG response to vaccination.