We assessed the effect of long-lasting inhibition of gastric acid secretion on basal and meal-stimulated serum gastrin and gastric acid secretion in 37 patients on long-term maintenance treatment with H2 antagonists for severe relapsing and/or complicated duodenal ulcer disease. After a mean of 142 weeks (range, 28-324 weeks) of continuous treatment, gastric acid secretion, basal plasma gastrin, and gastrin response to a test meal were evaluated. All tests were performed a week after drug discontinuation to exclude rapidly reversible hypergastrinemia. Gastrin levels were above the normal range in seven patients (18.9%). After H2 antagonist were stopped for 6 weeks, basal gastrin returned to normal levels in all cases [from a median of 180 (range, 130-350) pg/ml to 58 (25-90) pg/ml] and peak meal-stimulated gastrin significantly decreased from a median of 500 pg/ml to 245 pg/ml (p = 0.02). In patients with hypergastrinemia, the discontinuation of H2 antagonists for 6 weeks led to a significant decrease of gastric acid secretion. Patients who developed hypergastrinemia spent more weeks on full-dose treatment and had more recurrences during therapy. The results of the present investigation demonstrate that a long-lasting inhibition of gastric acid secretion can induce, in a small percentage of patients, a reversible sustained hypergastrinemia and a consequent increase of acid secretion, which conceivably could lead to more frequent relapses of duodenal ulcer disease.