We applied the low-dose challenge (chronic) and reactivation following chemotherapy withdrawal (Cornell-like) TB models to mouse strains with genetically different susceptibility to and severity of Mycobacterium tuberculosis-triggered disease. Systemic infection caused by intravenous (i.v.) administration of approximately 70 cfus of M. tuberculosis H37Rv lead to chronic, persistent, non-lethal disease in genetically resistant B6 mice, but resulted in a fatal pathological process in the lungs of susceptible I/St animals. Thus, application of the identical experimental approach to genetically different murine hosts allows investigating both slowly progressive disease with the fatal outcome (I/St) and chronic life-span disease (B6). Under Cornell-like model conditions, both temporary eradication of cultivable bacilli from lungs and spleens due to chemotherapy and their re-appearance in organs following its withdrawal were demonstrated in mice of both strains. However, (i) reactivation occurred significantly earlier in I/St than in B6 mice; (ii) I/St mice survived not more than 6 month following chemotherapy withdrawal and demonstrated 100% TB relapse, whereas in B6 mice mortality did not exceed 50%, and no mycobacteria were recovered from some animals. I/St mice, with their genetically determined high TB severity, provide a more reliable tool for modeling TB relapse after chemotherapy withdrawal than mice of more resistant strains.