Histomorphometric, electron microscopic, and cell kinetic studies of gastric mucosa were performed in 12 healthy men treated with 100 micrograms of 15(R)-15-methyl prostaglandin E2 (PGE2) orally q.i.d. for 2 mo followed by 2 mo of placebo. Results were compared with 13 control subjects receiving placebo for 4 mo. After PGE2 administration, total antral mucosal thickness and antral and corpus foveolar thicknesses increased 36%, 44%, and 51%, respectively, over baseline values. The total number and height of the foveolar cells also increased. These morphologic changes reversed completely within 2 mo of stopping PGE2 therapy. After PGE2 administration, no evidence of mucosal inflammation or atypia was observed, nor was there any evidence of ultrastructural changes in the overall appearance of the parietal and gastrin cells. The increased thickness of the gastric mucosa could not be explained by alteration of the proliferative activity, as the labeling index and localization of the proliferative compartment remained unchanged after PGE2 therapy. Presumably PGE2 retards senescence and exfoliation of epithelial cells, which explains the foveolar expansion in the presence of unaltered proliferation.