The hypothesis that fat increases esophageal sensitivity to acid was tested in eight patients with gastroesophageal reflux disease and 11 healthy subjects. Protocol 1 included randomized intragastric infusions of saline or Lipofundin S 20% (306 kcal) on two separate days, followed after 30 and 90 min by an 8 ml/min intraesophageal infusion of 0.1 N HCl. The time to the onset of heartburn and the maximum heartburn score by visual analog scale during the acid infusion were similar after intragastric saline (2 min and 29.5 mm, medians) and fat (2 min and 20.5 mm). Protocol 2 included two 8 ml/min intraesophageal infusions of 0.2 N HCI diluted in an equal volume of saline or Lipofundin S 20% at a time interval of 10 min in randomized order. The time to the onset of heartburn and the maximum heartburn score were unaffected by the presence of fat in the esophageal infusate (2.5 min and 53 mm without vs 1.5 min and 49 mm with fat). We conclude that fat does not increase esophageal sensitivity to acid.