Infection by Mycobacterium tuberculosis (MTB) induces human alveolar macrophage (AMφ) apoptosis by a TNF-α-dependent mechanism. The apoptotic response is postulated to be a defense mechanism, limiting the growth of this intracellular pathogen. Consistent with that model, recent studies showed that the virulent MTB strain H37Rv induces substantially less AMφ apoptosis than the attenuated strain H37Ra. We now report that AMφ infection with either H37Rv or H37Ra induces comparable levels of TNF-α measured by ELISA but that TNF-α bioactivity is reduced in supernatants of H37Rv-infected AMφ. Differential release of soluble TNFR2 (sTNFR2), with formation of inactive TNF-α-TNFR2 complexes accounted for the difference in TNF-α bioactivity in these cultures. Release of sTNFR2 by H37Rv-infected AMφ was IL-10 dependent since it was inhibited by neutralizing anti-IL-10 Ab. Thus, the effect of TNF-α produced by AMφ following infection can be modulated by virulent MTB, using IL-10 as an upstream mediator.