This study deals with the nonsteroid antiinflammatory drug indomethacin, a prostaglandin synthesis inhibitor, in the treatment of carcinogen-induced colonic tumors in rats. CD-Fischer rats were given an intrarectal instillation of methylnitrosourea (2 mg, three times a week for the first to the fifth week) in order to produce colonic tumors. Thereafter, a long-term treatment with an i.p. injection of indomethacin (2.5 mg/kg body weight, three times a week) was started at the 11th week, before the tumors developed. At autopsy, after the 15-week treatment with indomethacin, the colonic tumor incidence was significantly lower in treated rats than in vehicle-treated or untreated control rats. However, the 10-week cessation of treatment following this effective dosage led to a rapid development of tumors. In another experimental group of rats in which tumors were detected endoscopically, when treatment was initiated late, at the 26th week, for 10 weeks, tumor incidence and number were not altered. The data suggested that indomethacin inhibited the development of colonic tumors but did not reject or kill the growing tumors. It is postulated that indomethacin treatment may effectively prevent the development of colonic cancer in patients at high risk of colonic adenomatosis and carcinomatosis.