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Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) can preferentially initiate apoptosis in malignant cells with minimal toxicity to normal cells. Unfortunately, many human cancer cells are refractory to TRAIL-induced apoptosis through many unknown mechanisms. Here, we report that TRAIL resistance can be reversed in human bladder cancer cell lines by treatment with sulforaphane (SFN), a well-known chemopreventive isothiocyanate in various cruciferous vegetables. Combined treatment with SFN and TRAIL (SFN/TRAIL) significantly induced apoptosis concomitant with activation of caspases, loss of mitochondrial membrane potential (MMP), Bid truncation, and induction of death receptor 5. Transient knockdown of Bid prevented collapse of MMP induced by SFN/TRAIL, consequently reducing apoptotic effects. Furthermore, SFN increased both the generation of reactive oxygen species (ROS) and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is an anti-oxidant enzyme. Interestingly, TRAIL effectively suppressed SFN-mediated nuclear translocation of Nrf2, and the period of ROS generation was more extended compared to that of treatment with SFN alone. In addition, silencing of Nrf2 increased apoptosis in cells treated with SFN/TRAIL; however, blockade of ROS generation inhibited apoptotic activity. These data suggest that SFN-induced ROS generation promotes TRAIL sensitivity and SFN can be used for the management of TRAIL-resistant cancer.SFN sensitizes TRAIL-mediated apoptosis in TRAIL-resistant bladder cancer cells.SFN-mediated TRAIL sensitization requires Bid cleavage, leading to apoptosis.SFN enhances DR5 expression, resulting in cell death.SFN/TRAIL increases ROS generation in spite of Nrf2 activation.TRAIL helps to sustain SFN-mediated ROS generation.