The host response to infection in humans is multifactorial and involves the complex interaction between two genomes (the host and the pathogen) and the environment. Using an experimental mouse model of chronic infection, we have previously identified the individual effect of three significant and one suggestive quantitative trait loci (QTLs) (Ses1, Ses2, Ses3 and Ses1.1) on Salmonella Enteritidis persistence in target organs of 129S6/SvEvTac mice. Congenic strain construction was performed by transferring each of these QTLs from C57BL/6J onto the 129S6/SvEvTac background, and phenotypic analysis confirmed that Ses1 and Ses1.1 contribute to bacterial clearance. Additional QTLs regulating Salmonella carriage in 129S6/SvEvTac mice were identified using a two-locus epistasis QTL linkage mapping approach conducted separately in females and males. The epistatic model for females included the individual effect of Ses3 and two significant interactions (Ses1-D7Mit267 and Ses1-DXMit48) accounting for 47% of the total phenotypic variance. The model for males included the individual effect of Ses1.1, three interactions (Ses1-D9Mit218, D2Mit197-D4Mit2 and D3Mit256-D13Mit36) and explained 47% of the phenotypic variance. Our results suggest that the oligogenic nature of Salmonella persistence and epistasis are important constituents of the genetic architecture of the host response to chronic Salmonella infection.