This single-blind crossover trial compared the effects of single oral doses of two antacids on esophageal and gastric pH in subjects with heartburn. Gastric and esophageal pH were assessed in 83 subjects from 1 h before to 4 h after a refluxogenic meal. Subjects received two chewable tablets of a high-potency aluminum/magnesium hydroxide [Al(OH)3/Mg(OH)2] formulation (Mylanta Double-Strength®) or a calcium carbonate [CaCO3] formulation (Tums E-X®), or placebo 1 h after the meal. Both antacid formulations significantly increased esophageal pH, as compared with placebo. Onset of action was faster with the Al(OH)3/Mg(OH)2formulation than with the CaCO3in 41 subjects, slower in 13 subjects, and identical in 29 subjects. Area under the esophageal pH–time curves after dosing were significantly greater for Al(OH)3/Mg(OH)2than for CaCO3(p< 0.05) and significantly greater for CaCO3than for placebo (p< 0.05). The duration of Al(OH)3/Mg(OH)2action in the esophagus was 82 min and 60 min for CaCO3(p< 0.05). In the stomach, only Al(OH)3/Mg(OH)2increased gastric pH compared with placebo. After ingestion of calcium carbonate, gastric pH usually remained at or below placebo values, a finding consistent with a calcium carbonate-induced “acid rebound.‘’ The duration of Al(OH)3/Mg(OH)2action in the stomach was 26 min. These findings demonstrate the efficacy and relative superiority of this particular aluminum/magnesium hydroxide formulation compared with the calcium carbonate preparation at increasing esophageal and gastric pH. However, the magnitude and duration of action of both antacids on esophageal pH, in contrast to minimal effects on gastric pH, suggest strongly that the lower esophagus is the primary site of antacid activity in relief of heartburn.