Background Although most patients with gastro-oesophageal reflux disease (GERD) benefit from proton pump inhibitor (PPI) therapy, some experience only partial symptom relief. Aim To determine the prevalence of partial heartburn response to PPIs and its impact on health-related quality of life. Methods Four randomised, double-blind studies in adults with reflux disease compared esomeprazole 40 mg/day or 20 mg/day with omeprazole 20 mg/day, or esomeprazole 40 mg/day with pantoprazole 40 mg/day. Patients with heartburn on ≥4 days during the 1-week recall period at baseline were included. Partial response was defined as heartburn on ≥3 days during the last treatment week and reduced heartburn frequency after 4 weeks of treatment compared with baseline. Results The analysis included 2645 patients with non-erosive reflux disease (mean age: 48.8 years; 54.4% women) and 3151 patients with reflux oesophagitis (mean age: 50.6 years; 37.1% women). At baseline, most patients reported heartburn on 5-7 days (non-erosive reflux disease: 82.2%; reflux oesophagitis: 86.8%). Partial heartburn response occurred in 19.9% of patients with non-erosive reflux disease and 14.0% with reflux oesophagitis. Defining partial response as heartburn on ≥2 days increased these rates to 26.2% and 19.3%, respectively; defining partial response as heartburn of moderate or severe intensity on ≥3 days decreased these rates to 6.4% and 5.3%, respectively. Nonresponse to PPIs was rare (non-erosive reflux disease: 2.4%; reflux oesophagitis: 1.4%). Conclusion Using our conservative definition, partial heartburn response to proton pump inhibitor therapy occurred in 14-20% of gastro-oesophageal reflux disease patients, more commonly in non-erosive reflux disease than in reflux oesophagitis.