Mucosal morphology and the balance between cell loss and cell renewal were analyzed during treatment with a non-ulcerative dose of indomethacin. All rats were treated twice daily by subcutaneous injection of 2 mg/kg indomethacin or the solvent. The following parameters were assessed: cell proliferation on day 3 (determination of in vitro [3H]thymidine incorporation), cell migration on days 1 and 3 (autoradiography), cell shedding on days 7 and 14 (measurement of the remaining DNA-bound mucosal radioactivity after in vivo labeling with [3H]thymidine prior to treatment), mucosal morphology on day 14 (light microscopy), ex vivo mucosal prostaglandin E2 on day 14, and serum gastrin on days 0, 7, and 14. Indomethacin treatment had no effect on serum gastrin levels but reduced mucosal prostaglandin E2. Indomethacin produced a significant increase of [3H]thymidine incorporation, cell migration, and loss of mucosal DNA-bound radioactivity in the corpus and, to a lesser degree, in the antrum. Morphologically, this led to a hyperplasia of parietal cells (+15%, P less than 0.05) and chief cells (+45%, P less than 0.01) in the corpus, but antral morphology remained unchanged. We conclude that indomethacin stimulates the turnover of gastric mucosal cells. In the corpus, but not in the antrum, proliferation exceeds shedding, thus leading to increased mucosal volume.