In this study, we assessed by a double-blinded, cross-over design the effect of intravenous and oral cisapride on esophageal motor activity during the late fed state in normal subjects. For the intravenous study, subjects were given placebo or 10 mg cisapride randomly, while in the oral study, they randomly received placebo or cisapride at 5, 10, or 20 mg. Cisapride given intravenously or orally caused a significant increase in resting LES pressure. The increase in LES pressure after oral administration was significant only after the 20 mg dose. Esophageal-body peristaltic amplitude, determined for all smooth-muscle sites, showed a modest but significant increase of approximately 10 mm Hg after intravenous cisapride, whereas no significant increase occurred after oral cisapride. Propagation time of peristalsis was unaffected by intravenous or oral cisapride. Side effects of treatment were minimal and at no time necessitated cessation of the study. We conclude that in healthy subjects during the late fed period, (1) cisapride at 10 mg intravenously or 20 mg orally increased resting LES pressure and (2) at 10 mg intravenously, but at no oral dose, cisapride increased peristaltic amplitude without affecting propagation time. The potentiating effect of cisapride on LES pressure suggests that cisapride could have an ancillary role in the therapy of gastroesophageal reflux disease.