The purpose of this study was to investigate the effects of cimetidine and ranitidine on human lower esophageal sphincter pressure (LESP) and plasma levels of gastrin in all phases of the interdigestive motor complex and after a test meal. In a random, double-blind manner, placebo, cimetidine (1.0 mg/kg X h), and ranitidine (0.16 mg/kg X h) were administered by intravenous infusion to nine healthy volunteers. By using a sleeve catheter assembly, LESP was constantly monitored, as were esophageal, fundic, antral, and duodenal pressures. Considerable minute-to-minute and interdigestive motor phase-related LESP variations were observed. Cimetidine and ranitidine decreased the interdigestive LESP, but did not abolish the gradual increase in LESP from phase I to phase III. During the first 2 h after the meal, cimetidine and ranitidine had no significant effect on LESP. Plasma gastrin levels were increased by cimetidine and ranitidine, both in the interdigestive and in the postprandial state. The results indicate that the effect of H2-blockers on LESP is not gastrin-mediated. The results further indicate that, in studies on the effects of drugs on LESP, prolonged recording of LESP in all motor states is a prerequisite.