Mycobacterium tuberculosis and M. avium complex strains given intramacrophage passage (I-type) were compared with those cultured in a liquid medium (E-type) for their drug susceptibilities when they were replicating in Mono-Mac-6 macrophages or A-549 cells. Their intracellular susceptibilities to rifalazil, clarithromycin, and levofloxacin were decreased more in I-type organisms than in E-type organisms, except that their rifalazil susceptibility inside A-549 cells was markedly increased in I-type organisms.