Tuberculosis (TB) remains a global health threat. Although it is generally accepted that TB results from intensive cross-talk between the host and the pathogen Mycobacterium tuberculosis, underlying mechanisms remain elusive. The first evidence of human polymorphisms related to susceptibilities to distinct M. tuberculosis lineages has been gathered. Confrontation of limited host resistance with heightened bacterial virulence forms a most hazardous combination. We investigated extreme combinations, confronting inducible nitric oxide synthase-deficient (iNOS(-/-)) and wild-type (WT) mice with 2 related M. tuberculosis strains that differ markedly in virulence, namely, the M. tuberculosis laboratory strains H37Rv and H37Ra. We provide evidence that deregulated chemokine signaling and excessive neutrophil necrosis contribute to disproportionate neutrophil influx and exacerbated TB in iNOS(-/-) mice infected with virulent M. tuberculosis (strain H37Rv), whereas resistant and susceptible mice controlled attenuated H37Ra equally well. Thus, a combination of host susceptibility and M. tuberculosis virulence determines the role of iNOS in the protection and control of inflammation.