Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, and it has been shown that many human cancer cell lines are refractory to TRAIL-induced cell death. However, the molecular mechanisms underlying resistance are unclear. In this study, we show that TRAIL resistance is reversed in human hepatoma cells by genistein, an isoflavone found in soy products. Synergistic induction of apoptosis in cells treated with genistein plus TRAIL was associated with cleavage of Bid, a proapoptotic BH3-only protein. Silencing of Bid expression reduced decreases in mitochondrial membrane potential and reduced apoptosis in cells treated with genistein and TRAIL, confirming that Bid cleavage is required for the response. Pretreatment with caspase-3 and caspase-8 inhibitors reduced cotreatment-induced apoptosis. However, treatment with TRAIL alone induced caspase-8 activity that was not different than TRAIL plus genistein; both effectively induced Bid cleavage. These data suggest that genistein abolishes resistance to the Bid cleavage of TRAIL, and that genistein does not interfere with signals upstream of Bid in hepatoma cells.