Bcl-2 inhibits apoptosis induced by a variety of death stimuli but does not completely inhibit Fas-mediated apoptosis. We have previously shown that a HeLa-derived cell line lacking mitochondrial DNA (mtDNA) expresses Fas at a high level and apoptosis is easily induced using a low concentration of an anti-Fas antibody. In this study, overexpression of Bcl-2 in the mtDNA-less cells completely blocked Fas-mediated apoptosis, and this was not due to a depression of the enhanced Fas expression. These findings suggest that the Fas-mediated apoptotic pathway is directly linked to Bcl-2 protection in the cells with an accompanying mitochondrial dysfunction.