It has been reported that activation of sphingomyelin pathway and nonsteroidal anti-inflammatory drugs (NSAIDS) inhibit the promotion of colon carcinoma. Ceramide, a metabolite of sphingomyelin, and indomethacin were shown to induce apoptosis in colon carcinoma cells. However, the mechanisms of ceramide- and indomethacin-induced apoptosis in the colon carcinoma cells are not clearly elucidated. Recent studys showed that indomethacin-induced apoptosis in colon cancer cells through the cyclooxygenase-independent pathways, and that may be mediated by generation of ceramide. In this study, we compared effects of ceramide and indomethacin on important modulators of apoptotic processes in HT29 cells, a human colon cancer cell line. Ceramide and indomethacin induced apoptosis dose- and time- dependently. Ceramide and indomethacin increased stress-activated protein kinase (SAPK) activity, and decreased mitogen-activated protein kinase (MAPK) activity. The expression of Bak was increased by the treatment of ceramide and indomethacin. The expression of other Bcl-2 related proteins (Mcl-1, Bcl-XL, Bax) which were known to be expressed in colon epithelial cells was not changed during the ceramide- and indomethacin-induced apoptosis. Our results suggest that ceramide and indomethacin share common mechanisms for induction of apoptosis in HT29 cells.