Omeprazole, a potent inhibitor of acid secretion, is effective in adults with severe gastroesophageal reflux, but no such data are available on children. We studied 15 children in whom treatment with histamine (type 2) blockers and prokinetic agents had failed; 4 had also had one or more fundoplications. Their ages were 0.8 to 17 years (mean, 8.1 years) and weights were 7.5 to 30.7 kg (mean, 18.6 kg). Of the 15 children, 8 were neurologically handicapped. All patients had endoscopic and histologic evidence of esophagitis; most had esophagitis grade 3 to 4. Patients were initially given omeprazole at 10 to 20 mg; the dose was titrated upward until results of a subsequent 24-hour intraesophageal pH study was normal. Symptoms and signs abated and evidence of esophagitis diminished in all patients. Omeprazole was given for periods of 5.5 to 26 months (mean, 12.2 months). The effective total dose was 20 to 40 mg (0.7 to 3.3 mg/kg) in 11 patients, 10 mg (0.7 mg/kg) in 1 patient, and 60 mg (1.9 to 2.4 mg/kg) in 3 patients. The dosage range was 0.7 to 3.3 to mg/kg per day (mean, 1.9 mg/kg). Mildly elevated transaminase values in 7 patients and elevated fasting gastrin levels in 11 patients were present; in 6 of the 11, gastrin levels were 3 to 5.5 times the upper limit of normal. We found omeprazole to be highly effective in this group of patients with severe esophagitis refractory to other measures. We recommend a starting dose of 0.7 mg/kg as a single morning dose; the adequacy of reflux control is then determined by follow-up 24-hour intraesophageal pH studies. Omeprazole appears to be safe for short-term use, but further studies are needed to assess long-term safety because the significance of chronically elevated gastrin levels in children is unknown.