1 Pre-drug concentrations of both nucleotides were similar in patients with or without peptic ulceration. 2 The effect of a singly infusion or repeated oral administration of cimetidine on human gastric mucosal content of cyclic AMP and cyclic GMP was studied. 3 Biopsies from the body of the stomach were taken at endoscopy from patients who were participating in a clinical trial of the value of cimetidine in the treatment of duodenal ulcer. Cyclic nucleotide determinations and histological examinations were performed on biopsies taken before and after cimetidine treatment. 4 Gastric mucosal content of cyclic AMP was significantly increased (P less than 0.01) 20 min after intravenous infusion of 200 mg cimetidine. There was also a significant increase (P less than 0.01) in gastric mucosal cyclic AMP following administration of the drug orally for 28 days. No alterations in gastric mucosal histology were observed following cimetidine treatment. 5 Gastric mucosal content of cyclic GMP was not altered by intravenous drug infusion, or by chronic treatment.