Adenylate cyclase (AC) in response to prostaglandin E₂ (PGE₂) and histamine was studied in morphologically different biopsy specimens from human gastric mucosa. The activities of the enzyme were log-normally distributed and did not differ between males and females. PGE₂ activated AC in a concentration-dependent manner in normal gastric mucosa (n = 57), chronic superficial gastritis (GI, 18), chronic gastritis with beginning atrophy (GII, 10), chronic atrophic gastritis (GUI, 24), gastric ulcer (GU, 39), duodenal ulcer (DU, 32), and biopsies of patients operated according to Billroth II (BII, 20) and was most efficacious in GUI and BII. Histamine, which was studied in normal gastric mucosa (n = 27), DU (n = 20), GU (n= 13), and BII (n = 18), stimulated AC most efficaciously and potently in DU, was less effective in normal gastric mucosa and GU, and had no effect at all in BII. Cimetidine treatment of DU patients did not change the PGE₂ action, while the degree of stimulation by histamine was reduced. The data indicate characteristic differences of the PGE₂- and histamine-sensitive AC in the mucosal samples of these patients.