The mechanism whereby bile acids promote colon tumor development was studied. Bile acids increase intestinal ornithine decarboxylase (ODC), an effect that is suppressed by indomethacin, an inhibitor of prostaglandin (PG) synthesis. Male Sprague-Dawley rats were pretreated with 0.002% indomethacin solution in drinking water for 3 days, then given a single intrarectal instillation of 20 mg of deoxycholate and/or 1 mg of PGE2. Four hours later, the rats were killed, and the ODC activity was measured in the mucosa of the distal large bowel. ODC was significantly lower in rats given indomethacin plus deoxycholate than in those given deoxycholate alone, but it was significantly higher in rats treated with indomethacin and PGE2 plus deoxycholate. Without deoxycholate, indomethacin plus PGE2 did not elevate ODC compared with indomethacin alone or no treatment. Indomethacin reduced the colonic mucosal PG level. Thus, PGE2 mediates the deoxycholate-induced colonic mucosal ODC activity, and overcomes the inhibition of this enzyme activity by indomethacin. It is concluded that the anti-promoting effect of indomethacin in colon carcinogenesis, previously demonstrated, may result from the indomethacin inhibition of PG synthesis.