Non-steroidal anti-inflammatory drugs (NSAIDs) have cancer preventive and tumor regressive effects in the human colon, perhaps due to their capability to induce apoptosis of the colon cancer cells. Here, we report that indomethacin induced the expression of Nur77 which has been implicated in activation-induced apoptosis of T-lymphocytes, in a colon cancer cell line, HCT-15. The transcript- and protein-level, the transcriptional activity of Nur77 promoter, and the DNA binding of Nur77 were significantly induced following indomethacin treatment. Among the two potential trans-acting factors that activate Nur77-promoter, indomethacin induced DNA binding and reporter gene activity of AP-1, but not that of related serum response factor (RSRS), suggesting that the transcriptional induction of Nur77 may be mediated through activation of AP-1. Further, we showed that alltrans-RA repressed the induction of Nur77 as well as the apoptosis-induced by indomethacin, providing evidence that transcriptional induction of Nur77 may be an important mechanism by which indomethacin induces apoptosis in colon cancer cells.