OBJECTIVE Eicosanoids (prostaglandins and leukotrienes) may contribute to the clinical manifestations of gastroesophageal reflux disease (GERD). In this cross-sectional study, our purpose was to assess the role of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in the clinical, endoscopic, and histological manifestations of GERD. METHODS Using RIA, we measured ex vivo LTB4 and PGE2 content in esophageal mucosal biopsies from 141 patients with or without gastroesophageal reflux disease who underwent upper endoscopy. Patients were classified as normal symptomatic controls(n = 70), esophagitis stages 1-4 (n = 60), and Barrett's esophagus (n = 11), using clinical, endoscopic, histological, manometric, and esophageal 24-h ambulatory pH criteria. RESULTS Mean LTB4 levels were significantly higher in both endoscopically and histologically identified erosive esophagitis and Barrett's esophagus patients, compared with normal controls. In contrast, PGE2 levels did not differ significantly among endoscopic or histological groups. When eicosanoid levels and composite symptom score (frequency score x severity score summed over five symptoms) were analyzed, no significant associations were found between LTB4 or PGE2 levels and the composite symptom score. There was no correlation between tissue eicosanoid levels and either the degree of esophageal acid exposure by ambulatory pH monitoring or the lower esophageal sphincter resting pressure as assessed by esophageal motility. Treatment with omeprazole 20 mg by mouth daily for 6 wk significantly reduced both LTB4 and PGE2 levels (p < 0.05) and was associated with significant improvement of symptoms and the endoscopic and histological appearance of the esophagus in 25 patients. CONCLUSIONS These results suggest that LTB4, a prominent product of arachidonic acid metabolism in neutrophils, mediates the inflammatory phenomena of reflux esophagitis. The role of LTB4 and PGE2 in the induction of symptoms in patients with GERD and Barrett's esophagus remains unclear.