Background: A subset of patients with gastro-oesophageal reflux disease (GERD) does not achieve complete symptom resolution with proton pump inhibitor (PPI) therapy. The factors which affect response to PPI therapy in GERD patients remain unclear. Aims: To determine the prevalence and impact of irritable bowel syndrome (IBS) and psychological distress (PD) on GERD symptoms and disease-specific quality of life (QoL) before and after PPI therapy and to assess the same outcomes before and after PPI therapy in non-erosive reflux disease (NERD) and erosive oesophagitis (EO) GERD patients. Methods: Patients undergoing oesophago-gastroduodenoscopy (OGD) for heartburn were recruited. Participants completed validated surveys: Digestive Health Symptom Index, Reflux Disease Questionnaire, Quality of Life in Reflux and Dyspepsia and Brief Symptom Inventory (BSI). IBS was defined as >3 Manning criteria and PD as BSI score >63. At OGD, patients were classified as NERD or EO. Patients were treated with rabeprazole 20 mg/day for 8 weeks before completing follow-up surveys. Results: Of 132 GERD patients enrolled, 101 completed the study. The prevalence rates of IBS and PD were 36% and 41%, respectively. IBS independently predicted worse QoL before and after PPI therapy. PD independently predicted worse GERD symptoms and QoL before and after PPI therapy. There were no differences in symptoms or QoL between NERD and EO patients before or after PPI therapy. Conclusions: IBS and PD impacted GERD symptoms and QoL before and after PPI therapy. Symptoms and QoL before and after PPI therapy were similar in NERD and EO patients.