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. Although an important role of genetic variation of host in outcomes of tuberculosis infection is well documented, genetic determinants of susceptibility in immunocompetent individuals remain largely unknown due to complex multigenic control and significant impact of genes - environment interactions. Natural genetic variation of host resistance to MTB in immunocompetent inbred mice reflects heterogeneity among humans and allows stepwise dissection of the genetic control using a mouse model. Previously we characterized a mouse super-susceptibility locus (sst1) and mapped additional quantitative trait loci (QTLs) controlling anti-tuberculosis immunity, among which a QTL on chromosome 7 was most prominent. In this study we addressed a specific role of the chromosome 7 QTL and found that the chromosome 7 and sst1 loci independently control distinct mechanisms of host resistance to MTB, but the phenotypic expression of the chromosome 7 locus is significantly influenced by interactions with the sst1. While the sst1 locus is especially important in the lungs and the effect of the chromosome 7 locus is systemic, both loci affect macrophage-mediated control of virulent MTB in vivo. Their combined effect accounts for half of the dramatic difference in survival between the susceptible and resistant parental strains. Further genetic and functional dissection of the chromosome 7 locus to identify causal genetic variation will help untangle the genetic basis of tuberculosis susceptibility in immunocompetent hosts.