Mycobacterium avium is an intracellular microorganism that infects and multiplies within macrophages. Cell-mediated immunity plays an important role in host defense, and interleukin (IL)-12, which is produced mainly by macrophages, is critical for its development. In a mouse model of disseminated M. avium infection, genetically susceptible BALB/c mice had increased mycobacterial growth and decreased IL-12 expression and developed large and numerous granulomas. In contrast, resistant DBA/2 mice exhibited reduced mycobacterial burden with increased IL-12 expression and developed fewer and smaller granulomas. In susceptible mice with established M. avium infection, IL-12 replacement therapy resulted in persistent reduction of mycobacterial burdens. IL-12 itself, however, could not inhibit mycobacterial growth in vitro. By enhancing host defenses, IL-12 exerts a potent mycobactericidal activity in vivo with low toxicity. This suggests that IL-12 replacement therapy is rational for M. avium infection in susceptible hosts.