A new benzoxazinorifamycin, KRM-1648 (KRM), was studied for its therapeutic efficacy in combination with other antimicrobials against Mycobacterium avium complex infections in mice. When M. intracellulare-infected (intravenously) mice were given KRM, clarithromycin (CAM), sparfloxacin (SPFX), or ethambutol (EB) each alone or in combination, by gavage, once daily 6 times per week (streptomycin [SM] was given subcutaneously twice per week) from day 1, KRM + CAM exhibited combined efficacy in terms of reducing the incidence of gross lung lesions and the bacterial loads in the lungs and spleens. The addition of either EB or EB + SPFX to KRM + CAM increased the efficacy. Moreover, the multi-drug regimen of KRM + CAM + EB + SPFX or ofloxacin [OFLX]) was more efficacious than rifampicin (RMP) + CAM + EB + SPFX (or OFLX). In M. avium infection, KRM + clofazimine was the most efficacious among two-drug combinations tested followed by KRM + SM. KRM + CAM was considerably less effective against M. avium than against M. intracellulare infection. KRM + EB and KRM+OFLX failed to show such a combined effect.