This study was undertaken to determine the role of food in indomethacin-induced gastrointestinal lesions. Following a 24- or 48- fast, rats were given various amounts of rat Chow pellets or various types of diets (high-bulk non-nutritive diet, equicaloric liquid diet, or liquid diet containing cellulose) for 1 h. One half hour after the feeding, 30 mg/kg of indomethacin was administered subcutaneously, and 6 h later the animals were killed and gastrointestinal lesions measured. In the fasted rat, indomethacin produced lesions predominantly in the gastric corpus. In the rat that was fed Chow pellets, indomethacin produced lesions in both the gastric antrum and small intestine. By increasing food intake, the corpus lesions decreased while antral and intestinal lesions increased. In the rat that was fed cellulose or sawdust pellets, indomethacin produced lesions in all three areas. In contrast, indomethacin did not produce any lesions in the liquid diet group. However, when cellulose was added to the liquid diet, indomethacin produced lesions in both the antrum and small intestine, the lesions increasing in proportion to increasing concentrations of cellulose. It is concluded that in indomethacin-induced gastrointestinal lesions: (a) the nutritional component of food prevents the formation of corpus lesions, and (b) the solid component of food, whether nutritive or not, plays an essential role in the formation of antral and intestinal lesions.