Although the influence of selective cyclooxygenase (COX)‐2 inhibitors on the proliferation of colon adenocarcinoma cells have been the subject of much investigation, relatively little research has compared the effects of different COX‐2 inhibitors. Celecoxib strongly suppressed the proliferation of COX‐2 expressing HT‐29 cells at 10–40 μM. NS‐398 and nimesulide also inhibited cell proliferation, whereas rofecoxib, meloxicam, and etodolac did not. Only celecoxib induced apoptosis of HT‐29 cells, as detected on the basis of DNA fragmentation, TUNEL positivity, and caspase‐3/7 activation. DNA fragmentation was also increasd in COX‐2 non‐expressing cell lines (SW‐480 and HCT‐116) by exposure to celecoxib for 6–24 h. All six COX‐2 inhibitors suppressed the production of prostaglandin E₂ by HT‐29 cells, suggesting that the pro‐apoptotic effect of celecoxib was unrelated to inhibition of COX‐2. Inactivation of Akt might explain the differential pro‐apoptotic effect of these selective COX‐2 inhibitors on colon adenocarcinoma cells.