The effect of Lps on the resistance of mice to gram-negative infection was compared in two genetically different backgrounds; C3H and C57BL. To mimic the natural sequence of pathogenetic events, infection was induced via a mucosal surface (intravesically), with Escherichia coli which remained at the mucosal site and Salmonella typhimurium which invaded to e.g., livers and spleens. Susceptibility was assessed as the bacterial persistence in kidneys, bladders, livers, and spleens at various times after infection. The initial clearance of both bacterial species from the mucosal site was significantly impaired in Lps(d) mice both in the C3H and C57BL backgrounds. In the C57BL mice, additional unknown determinants conferred increased resistance to mucosal infection compared to the C3H mouse. For S. typhimurium, these resistance factors and alleles at the Lps locus dominated over Ity as determinants of resistance to mucosal infection. The Ity(s) genotype conferred a significant increase in the susceptibility only to systemic infection, especially in the Lps(d), Ity(s) mice. These results demonstrate an important difference between the genetic determinants of host resistance at mucosal and systemic sites, and emphasize the role of LPS induced host defense mechanisms for bacterial clearance from mucosal surfaces.