The production of transforming growth factor-β (TGFβI) by human monocytes (MN) infected with Mycobacterium tuberculosis and its effects on the intracellular fate of the organism were studied. M. tuberculosis infection of MN induced both expression of mRNA and secretion of tumor necrosis factor-α( TNFα) and TGFβ1 protein. Neutralizing antibody to TGFβ1 reduced the intracellular growth of M. tuberculosis. The growth-enhancing effects of TGFβI could not be explained by increased initial bacterial load. Preculture with TGFβI decreased uptake of M. tuberculosis. Exposure of MN to increasing concentrations of TGFβI before or after infection with M. tuberculosis accelerated intracellular bacterial replication. Both TNFα and interferon-ã (IFN-ã) limited mycobacterial replication. TGFβ1 (10 ng/ml.) abrogated the bacteriostatic effects of TNFα and IFN-ã. Within the infected focus, TGFβ1 produced by mononuclear phagocytes may play an important role in the pathogenesis of tuberculosis, in part by modulating the response to potentially protective cytokines such as TNFa and IFN-ã.