Indomethacin produces gastric corpus erosions in the fasted rat and antral ulcers in the refed rat. The purpose of this study was to determined the role of gastric acid and prostaglandins in the formation of these gastric lesions. Sprague-Dawley rats, 180-250 g, were fasted for 24 hr (fasted) or fed chow pellets for 1 hr after a 24 hr fast (refed). Thirty mg/kg indomethacin was administered s.c. after a 24 hr fast or 0.5 hr after the refeeding, and 6 hr later the animals were sacrificed. Cimetidine, in antisecretory doses, prevented the formation of corpus erosions in a dose dependent manner but only the largest dose of cimetidine, 100 mg/kg s.c. x 2, prevented the antral ulcer formation. Prostaglandin E2, in non-antisecretory doses, prevented both the corpus erosions and antral ulcers in a dose dependent manner. We conclude that: 1. Antral ulcer formation is less sensitive to cimetidine than corpus erosion formation. This suggests that either acid plays a minor role in antral ulcer formation or more cimetidine is required for acid inhibition in the refed rat. 2. A deficiency of endogenous prostaglandins is an essential factor in the formation of indomethacin-induced gastric lesions. However, an additional mechanism is needed to explain the variation in location and histology of lesions with different feeding conditions.