The aim of the present study was to examine the effects of nonselective (indomethacin) and selective cyclooxygenase-2 (COX-2) inhibitors (NS-398, nimesulide, and CAY10404) on cell growth, cell cycle distribution, and apoptosis in three human hepatocellular carcinoma cell lines (HepG2, HuH-6, and HA22T/VGH) with different characteristics of differentiation and biological behavior. The four COX inhibitors showed a dose-dependent growth-inhibitory effect in all the cell lines. No substantial arrests in the progression of the cells through the cell cycle were observed after treatment of HuH-6 or HA22T/VGH for 48 h with the various inhibitors. On the other hand, there were significant increases in apoptosis, with the highest effect of cell kill being seen after treatment with indomethacin, especially in HuH-6. Our findings support the suggestion that selective or, perhaps more efficiently, nonselective COX-2 inhibitors may have potential therapeutic effects in hepatocellular carcinoma. Further studies must be carried out to better determine the possible mechanisms of these effects.