The host response to Salmonella infection is controlled by its genetic makeup. Using the mouse model of typhoid fever, several genes were found to influence the outcome of Salmonella infection, including Nramp1 (Slc11a1). In order to improve our knowledge of genetic determinants of the mouse response to acute Salmonella Typhimurium infection, we performed a systematic screening of a set of A/J and C57BL/6J recombinant congenic strains (RCS) for their resistance to infection. While we knew that the parental strains differ in their susceptibility to Salmonella because C57BL/6J mice carry a non-functional allele at Nramp1, we hypothesized that other genes would influence the response to Salmonella and segregate in the RCS. We identified several RCS that showed a non-expected phenotype given their known Nramp1 genotype proving that the response to Salmonella in A/J and C57BL/6J mice is complex. Based on these findings, we selected two RCS for generation of fully informative F2 crosses, (AcB61 x 129S6) and (AcB64 x DBA/2J). Genetic analyses performed on these crosses identified five novel Salmonella susceptibility QTL mapping to chromosomes 3 (Ity4), 2 (Ity5), 14 (Ity6), 7 (Ity7) and 15 (Ity8). These results illustrate the genetic complexity associated with the mouse response to Salmonella Typhimurium.