The nonsteroid antiinflammatory drug indomethacin, a prostaglandin synthesis inhibitor, inhibited the development of carcinogen-induced large bowel carcinomas in rats. CD-Fischer rats were given carcinogenic pretreatment with intrarectal instillation of 2 mg of methylnitrosourea 3 times a week from the 1st to the 5th week, in order to produce large bowel tumors. Thereafter, peroral administration of a high or low dose of indomethacin dissolved in drinking water (20 micrograms or 10 micrograms indomethacin/ml tap water) for 15 weeks was started at the 11th week, before the tumors developed. At autopsy in the 26th week just after the completion of the 15-week treatment, the incidence of developing large bowel tumors was significantly reduced in treated rats, compared to untreated control rats; 17% or 14% vs. 67%. However, at autopsy in the 36th week, 10 weeks after cessation of the treatment, the development of tumors in treated rats was significantly increased. Thus, indomethacin inhibited the development of methylnitrosourea-induced large bowel tumors in rats. The effectiveness of peroral administration of indomethacin was comparable to that of intraperitoneal administration. It is postulated that treatment with this drug may effectively prevent the development of large bowel cancer in patients at high risk.