BACKGROUND Few studies have specifically addressed the management of the symptoms of gastro-oesophageal reflux disease, and there are no comparative data in this respect for acid pump inhibitors and prokinetic agents. METHODS Following endoscopy 424 patients presenting with heartburn as the predominant symptom of gastro-oesophageal reflux disease were randomized to treatment with omeprazole 20 or 10 mg once daily, or cisapride 10 mg four times daily, in a double-blind, double-dummy, parallel group, multicentre study. Symptoms and quality of life were assessed at 4 weeks. Patients still experiencing heartburn continued therapy for a further 4 weeks and the assessments were repeated. RESULTS At 4 weeks, heartburn was resolved in 65% (95% CI: 57-73%), 56% (48-64%) and 41% (32%-49%) of patients treated, respectively, with omeprazole 20 mg and 10 mg once daily, and cisapride. Both omeprazole doses were significantly more effective than cisapride (P < 0.01). The same order of efficacy was observed regardless of the presence of erosive oesophagitis. Regurgitation and epigastric pain also improved to a greater degree with omeprazole than with cisapride. Quality of life was improved in all treatment groups, and the improvement in the reflux dimension of the Gastrointestinal Symptom Rating Scale (GSRS) score was significantly different between groups (P = 0.002). CONCLUSIONS Omeprazole 20 or 10 mg once daily is significantly more effective than cisapride in the resolution of heartburn, regardless of the presence of erosive oesophagitis, and this is accompanied by an improvement in patient quality of life.