Tuberculosis remains a significant global health problem: one-third of the human population is infected with Mycobacterium tuberculosis (MTB) and 10% of those are at lifetime risk of developing tuberculosis. In the majority of individuals infected, genetic determinants of susceptibility remain largely unknown due to complex multigenic control and the influence of genes—environment interactions. Genetic variation of host resistance to MTB in animal models reflects heterogeneity among humans. Stepwise dissection of these interactions will permit the deciphering of MTB's complex virulence strategy. Previously, we have characterized a mouse supersusceptibility locus (sst1) controlling antituberculosis immunity. In this study, eight host resistance quantitative trait loci (QTLs) were mapped that counter-balance the devastating effect of sst1, among which a QTL on chromosome 7 (Chr7) was most prominent. The Chr7 and sst1 loci independently control distinct resistance mechanisms to MTB, but their effects apparently converge on macrophages in remarkable synergy. Combining these resistance alleles on a C3HeB/FeJ-susceptible background reduced the lung pathology and improved survival after MTB challenge accounting for half of the difference between susceptible and resistant parental strains. These data reveal novel gene interactions controlling MTB resistance and will enable the identification of resistance gene (s) encoded within Chr7 locus.