Patients with duodenal ulcer disease received either a two hour pentagastrin infusion test or a similar test with the addition of a bolus of cimetidine, 200 mg, after one hour of pentagastrin. Pentagastrin induced secretion of acid and histamine, the secretion patterns of the two being similar. Total histamine output in the gastric aspirate in the first hour of pentagastrin infusion was related to total acid output (r = 0.58, p less than 0.01). A similar correlation was observed during the second hour of pentagastrin infusion (r = 0.61, p less than 0.05). Plasma histamine concentration rose to a peak coinciding with maximal acid secretion. After cimetidine blockade, gastric acid fell rapidly but gastric histamine output did not change. Plasma histamine concentration increased further. These results suggest that pentagastrin induced gastric histamine release is not affected by an acid inhibiting dose of cimetidine. Cimetidine caused histamine release into the circulation in both healthy volunteers and patients after total gastrectomy. The rise in plasma histamine concentration, however, was transient. In contrast, during pentagastrin infusion, the plasma histamine concentration remained high. These data support the hypothesis that histamine release induced by pentagastrin is a major stimulant of gastric acid secretion.