Addition of a nitroxybutyl moiety to diclofenac greatly reduces its damaging effects on the gastric mucosa without altering its ability to suppress prostaglandin synthesis and exert anti-inflammatory actions. The present study was performed in order to determine if this derivative of diclofenac, called nitrofenac, would also have less toxicity in the small and large intestine when administered repeatedly over a 1-2 week period. Healthy rats were given equimolar doses of diclofenac (10 mg/kg) or nitrofenac (15 mg/kg) twice daily for up to two weeks. All 10 rats receiving diclofenac died prior to completion of the study, exhibiting massive small intestinal ulceration and perforation. No deaths were observed in the rats treated with nitrofenac, and the only small intestinal abnormality observed was diffuse hyperemia. As nonsteroidal anti-inflammatory drugs have been shown to exacerbate colitis, we compared the effects of twice daily treatment with diclofenac (1-10 mg/kg) or nitrofenac (1.5-15 mg/kg) for 1 week in rats in which colitis had been induced with trinitrobenzene sulfonic acid. Diclofenac administration resulted in mortality which increased dose-dependently (e.g. 86% at 5 mg/kg) and was associated with perforation of the colon. Mortality was not observed with nitrofenac at doses of 1.5 or 7.5 mg/kg, while at 15 mg/kg the mortality rate was 33%. None of the doses of nitrofenac significantly augmented colonic injury or granulocyte infiltration (measured by myeloperoxidase activity). Suppression of colonic prostaglandin E2 synthesis was comparable with equimolar doses of diclofenac and nitrofenace. These studies demonstrate that nitrofenac has markedly reduced intestinal toxicity in healthy and colitic rats when compared to diclofenac.