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In the present study, the experimental model of Mycobacterium leprae infection in the foot pads of BALB/c mice was used to investigate the effects of BCG administration on tumor necrosis factor-alpha (TNF-alpha) production and granuloma development. It was observed that mice intravenously infected with BCG 7 months after M. leprae inoculation into the foot pads presented a more effective mycobacteria clearance, revealed by a significant reduction of BCG-colony forming units in the spleen and by the reduction of acid-fast bacilli (AFB) in the foot pads. BCG infection at the peak of M. leprae infection also modulated the granulomatous response to M. leprae by converting mononuclear granulomas into an epithelioid-cell granuloma. Furthermore, lower TNF-alpha serum levels were detected in M. leprae-infected mice when compared to mice infected with M. leprae + BCG. An analysis of the TNF-alpha gene expression in the spleen by semiquantitative reverse transcription-polymerase chain reactions (RT-PCR) demonstrated that co-infection with BCG induced an earlier expression of TNF-alpha mRNA than in M. leprae-infected mice. The numbers of TNF-alpha-positive cells and apoptotic cells were also enhanced in epithelioid versus non-epithelioid granulomas. As a whole, the data suggest that co-infection of M. leprae-infected mice with BCG modulates TNF-alpha synthesis which, in turn, leads to induction of protective epithelioid granuloma formation in the foot pads and subsequent mycobacterial clearance. Macrophage differentiation into epithelioid cells, in association with the enhancement of TNF-alpha production at the granuloma site, may represent a triggering signal that induced apoptosis in these cells, leading to mycobacterial elimination. Moreover, the rate of apoptosis in epithelioid granulomas may well be related to the extent of immunopathologically mediated tissue damage.