A zone of increased intraluminal pressure exists at the gastroesophageal junction in man and is believed to act as a physiologic sphincter. Increasing this lower esophageal sphincter (LES) tone is an accepted and useful method in preventing gastroesophageal reflux. The effects of LES tone were studied in 10 healthy volunteers receiving sequential intravenous injections of atropine, 0.6 mg, or domperidone, 10 mg, followed by domperidone, 10 mg, or atropine, 0.6 mg. The order of drug administration was randomized during the first study. Each volunteer was studied a second time, 1 week later, when the order of drug administration was reversed from the first. Administration of atropine decreased mean LES pressure by 12.6 cm H2O (p < 0.001). Subsequent injection of domperidone restored LES tone to near normal. In contrast, initial injection of domperidone approximately 1 week later in the same subjects, mean LES pressure increased by 18.5 cm H2O (p < 0.001). Intravenous injection of atropine, thereafter, failed to decrease mean LES pressure significantly, LES pressure being sustained at a mean of 14.8 cm H2O above basal control levels (p < 0.005). Results of this study suggest that domperidone given prior to atropine, before induction of general anesthesia, may counteract the potentially deleterious effect of atropine on LES tone, and thereby reduce the chances of regurgitation and pulmonary aspiration of acid gastric contents.