Sixty patients who presented with erosive/ulcerative refractory reflux esophagitis were randomized to receive a 4- to 8-week treatment with omeprazole 20 mg daily, or ranitidine 150 mg twice daily. Patients not healed after treatment were given the same drugs at doubled doses for a second period of equal duration. Patients still unhealed after this received open treatment with omeprazole 20 mg twice daily for a third period of 4 to 8 weeks. Endoscopic assessment and clinical and laboratory evaluation were performed every 4 weeks until there was complete esophageal mucosal repair. After 4 weeks, complete healing was observed in 50% of patients on omeprazole 20 mg daily, compared with 20.7% on ranitidine 150 mg twice per day (p < 0.01). After 8 weeks, the figures were 79.3% versus 34.5% (p < 0.5). With doubled doses after 4 weeks, complete healing was achieved in 96.6% of patients on omeprazole 40 mg daily, compared with 64.2% on ranitidine 300 mg twice per day (p < 0.05). The eight still "refractory" patients (one omeprazole, seven ranitidine) healed completely with 8 more weeks of omeprazole 20 mg twice daily. Patients treated with omeprazole experienced faster relief of heartburn, which disappeared in 60% of patients after 4 weeks, as compared to 21% of patients treated with ranitidine (p < 0.006). Apart from the mode of treatment, the only factor that proved to be related to healing at multivariate analysis was the pretreatment severity of gastroesophageal reflux, as measured by esophageal pH monitoring. Our study confirms that omeprazole, even at a low dosage, is the choice for refractory reflux esophagitis.