Epidemiological studies have shown a significant inverse association between intake of COX inhibitors and the risk of colorectal cancer. The present study was conducted to determine whether SC560 (a COX-1 selective inhibitor), NS398 (COX-2 selective), SC58125 (COX-2 selective), nimesulide (COX-2 selective) and indomethacin (COX non selective), might exert chemopreventive influence on diethylnitrosamine (DEN) initiated hepatocarcinogenesis in a medium-term liver carcinogenesis bioassay in F344 male rats. Contrary to expectation, in the SC58125 treated group, the numbers and areas of glutathione S-transferase placental form (GST-P) positive liver cell foci were increased significantly, along with liver weights. In the other groups no significant changes were evident. Histopathologically, liver cells of SC58125 treated rats showed hypertrophy similar to cases with phenobarbital treatment. For further clarification, Experiment 2 was performed. After 2 weeks on test chemicals and basal diet, animals underwent histopathological, microarray and quantitative RT-PCR assessment. CYP 2B1 and 3A1 were found to be induced, again similar to phenobarbital cases. Although COX-2 selective inhibitors are clearly good candidates for chemoprevention, it is necessary to examine them carefully for any adverse toxic effects at the whole body level before considering their application as chemopreventive agents.