Experimental infection of mice with Sendai virus (SeV) is frequently used as a model of viral pathogenesis of human respiratory disease. To understand the differences in host response to SeV among mice strains, we carried out genetic mapping studies in DBA/2 (D2) (susceptible) and C57BL/6 (B6) (resistant) mice. F(1), F(2), and N(2) backcrossed mice were generated and examined for their disease resistance and susceptibility. For the determination of virulence, percentage body weight loss and survival time were used as phenotypes. We, then, carried out a genome wide scan on 108 backcrossed mice for linkage with percentage body weight loss as phenotype. A major quantitative trait locus (QTL) showing significant linkage was mapped to the distal portion of Chr 4 (SeV1). In addition, two other QTLs showing suggestive statistical linkage were also detected on Chr 8 and 14. We, further, performed genome scan for interactions with least squares analysis of variance of all pairs of informative makers in backcrossed progenies. We identified a highly significant epistatic interaction between D3Mit182 and D14Mit10, then denoted as SeV2 and SeV3, respectively, and the latter was the same locus showing a suggestive level on Chr 14 in QTL analysis. Considered genotypes of these three loci, we could account for more than 90% of genetic effect on the differential response to SeV infection between B6 and D2 mice. These findings revealed a novel gene interactions controlling SeV resistance in mice and will enable the identification of resistance genes encoded within these loci.