Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) has recently been shown to be induced by nonsteroidal anti-inflammatory drugs (NSAIDs) and to have proapoptotic and antitumorigenic activities. Although sulindac sulfide induced apoptosis in sinonasal cancer cells, the relationship between NAG-1 and NSAIDs has not been determined. In this study, we investigated the induction of apoptosis in sinonasal cancer cells treated by various NSAIDs and the role of NAG-1 expression in this induction. The effect of NSAIDs on normal human nasal epithelial (NHNE) cells was also examined to evaluate their safety on normal cells. Finally, the in vivo anti-tumorigenic activity of NSAIDs in mice was investigated. In AMC-HN5 human sinonasal carcinoma cells, indomethacin was the most potent NAG-1 inducer and caused NAG-1 expression in a time- and dose-dependent manner. The induction of NAG-1 expression preceded the induction of apoptosis. Conditioned medium from NAG-1-overexpressing Drosophila cells inhibited proliferation of sinonasal cancer cells and induced apoptosis. In addition, in NAG-1 small interfering RNA-transfected cells, apoptosis induced by indomethacin was suppressed. In contrast, NAG-1 expression and apoptosis were not induced by NSAIDs or conditioned medium in NHNE cells. Furthermore, indomethacin induced a dose-dependent in vivo increase in the expression of NAG-1 mRNA in the mice tumors and the volume of xenograft tumors of AMC-HN5 cells in indomethacin-treated nude mice was reduced compared to that in control mice. In conclusion, indomethacin exerts proapoptotic and antitumorigenic effects in sinonasal cancer cells through the induction of NAG-1 and can be considered a safe and effective chemopreventive agent against sinonasal cancer. © 2007 Wiley-Liss, Inc.