Transcription factor NF-kappaB plays a pivotal role in cancer cells in the resistance to apoptosis, since NF-kappaB is frequently activated in many primary carcinoma cells. Indeed, several NF-kappaB inhibitors are found to be promising anti-cancer agents. However, some anti-cancer agents activate NF-kappaB signals and may reduce their potential, including tumor necrosis factor (TNF)-alpha. Recently, the nonsteroidal anti-inflammatory drug (NSAID) sulindac and its metabolites have been shown to inhibit the NF-kappaB-mediated survival signals through inhibition of IKK-beta by their direct interaction. We thus investigate whether sulindac and its metabolite can augment TNF-alpha-mediated apoptosis in human carcinoma cells and be applicable for in vivo clinical usage. We here demonstrate that sulindac inhibited TNF-alpha-mediated NF-kappaB activation and greatly enhanced TNF-alpha-induced apoptosis in human gastric MKN45 and cervical HeLa carcinoma cell lines. The in vivo tumor growth of MKN45 cells was most strongly inhibited by a combination of TNF-alpha with sulindac compared with TNF-alpha or sulindac alone. Moreover, we demonstrate that sulindac sulfide further augmented TNF-alpha-mediated apoptosis. Our data strongly suggest that combination therapy of TNF-alpha with sulindac and its metabolites may sensitize cancer cells to TNF-alpha and augment its pro-apoptotic potential. Therefore, in combination with sulindac or its metabolites, TNF-alpha may become a potentially useful anti-cancer agent to suppress tumor.