Medical treatment of duodenogastroesophageal reflux in postgastrectomy patients has been disappointing. Using ambulatory esophageal bilirubin monitoring, we evaluated the efficacy of cisapride in this disorder. Ten chronically symptomatic partial gastrectomy patients (5 Billroth I, 5 Billroth II; 8 men; average age 57) with duodenogastroesophageal reflux were randomized to four weeks of either placebo or cisapride (20 mg four times a day) in a double-blind crossover study. Significantly improved patients continued to take cisapride for an additional four months. Duodenogastroesophageal reflux was assessed at baseline and after four weeks on each therapy. Daily diary recorded symptoms and mean monthly scores were determined. Global symptom improvements were assessed at the end of each treatment period. Compared to placebo, cisapride significantly (P < 0.05) decreased duodenogastroesophageal reflux. Overall symptom improvements were assessed at the end of each treatment period. Compared to placebo, cisapride significantly (P < 0.05) decreased duodenogastroesophageal reflux. Overall symptoms improved in 70% of patients on cisapride compared to 10% on placebo (P < 0.01). Mean monthly scores significantly (P < 0.05) improved for abdominal pain, regurgitation, and belching. These symptoms remained improved after four months of chronic therapy. We conclude that cisapride significantly reduces duodenogastroesophageal reflux and results in short- and long-term symptom improvements in postgastrectomy patients and that cisapride offers the first successful medical therapy for duodenogastroesophageal reflux in postgastrectomy patients.