The effects on fasting serum gastrin concentrations of hourly doses of magnesium and aluminum hydroxide antacid, with and without intravenous cimetidine, were determined in 8 patients with duodenal ulcer disease. Gastrin levels rose significantly over 10 h when antacid was given either as a bolus of 30 ml every hour or as a constant infusion of 0.5 ml/min (36 +/- 5 pg/ml and 33 +/- 6 pg/ml to 108 +/- 32 pg/ml and 109 +/- 22 pg/ml, respectively, p less than 0.05). This effect was specific for some component of the antacid and not for neutralization of acid per se, inasmuch as sodium bicarbonate, infused to keep gastric pH at levels at or above those of antacid, produced no significant rise in serum gastrin concentration. When intravenous cimetidine was administered simultaneously with intragastric antacid, gastrin levels did not rise. This occurred even though intragastric pH levels were actually higher with cimetidine plus antacid than with antacid alone. The ability of intravenous cimetidine to block antacid-induced hypergastrinemia was counteracted by infusing simultaneously both hydrochloric acid and antacid into the stomach. Since hydrochloric acid reacts with magnesium and aluminum hydroxide to form ionic magnesium and aluminum chloride, cimetidine most likely blocks antacid-induced hypergastrinemia by reducing acid secretion from the stomach and thereby limiting the generation of ionic magnesium and aluminum.