Despite antibiotic therapy and vaccination programs, microbial diseases continue to be the leading cause of morbidity and mortality worldwide. The genetic basis of the host response to infection is complex, and its understanding has been facilitated through the study of mouse models of human infectious diseases. Genetic variation in resistance of mice to infection with Salmonella typhimurium has been recognized for over 50 years and shown to be a multifactorial trait. We have studied the genetic basis of resistance or susceptibility to infection with S. typhimurium in the wild-derived inbred mouse Mus musculus molossinus (MOLF/Ei). MOLF/Ei mice are extremely susceptible to infection with S. typhimurium despite the presence of resistance alleles at Nramp1 and Lps. To identify genes that modulate the expression of natural resistance or susceptibility to infection with S. typhimurium in MOLF/Ei, we have performed a genome-wide study using an F2 intercross between C56BL/6J and MOLF/Ei inbred mice. We have mapped three QTLs that significantly affect survival time following lethal infection with S. typhimurium. The Salmonella-resistant phenotype was linked to Nramp1 on proximal chromosome 1 (maximum lod score of 18.8 at D1Mcg4) and to a newly mapped region on mouse chromosome 11 (maximum lod score of 7.0 at D11Mit5). The third QTL conferred recessive susceptibility and was located on mouse chromosome 1, approximately 25 cM distal to Nramp1 (maximum lod score of 4.8 at D1Mit100).