The factors predisposing to the development of Barrett's esophagus in patients with gastroesophageal reflux disease are unclear. We compared symptoms, esophageal acid and alkaline exposure (pH < 2, < 3, < 4, and > 7), lower esophageal sphincter resistance, esophageal clearance function, the gastric secretory state, gastric emptying, and duodenogastric reflux in 15 patients with Barrett's esophagus with 24 patients with esophagitis and with 22 normal subjects. Compared with patients with esophagitis, patients with Barrett's esophagus had less heartburn and regurgitation but had an increased frequency and duration of reflux episodes and percent time pH less than 2, less than 3, less than 4, and pH greater than 7 on ambulatory 24-hour esophageal pH monitoring. This was associated with a decreased lower esophageal sphincter resistance, a decreased contraction amplitude in the distal area of the esophagus, an increased frequency of nonperistaltic contractions and contractions less than 30 mm Hg on 24-hour ambulatory esophageal motility monitoring, increased basal and stimulated gastric acid secretion, and a higher prevalence of excessive duodenogastric reflux. These data show that despite less symptoms patients with Barrett's esophagus have a markedly increased esophageal acid and alkaline exposure compared with patients with esophagitis. This appears to be because of persistent reflux of highly concentrated gastric acid and duodenal contents across a mechanically defective lower esophageal sphincter in combination with inefficient esophageal clearance function.