BACKGROUND: A simple and meaningful health-related quality of life (HRQoL) questionnaire for gastro-oesophageal reflux disease (GERD) patients is lacking. AIM: To develop and validate a disease-specific HRQoL instrument (GERD-QOL) for GERD patients. METHODS: An 18-item questionnaire was generated to measure the impact of GERD on sleep, exercise, diet, need for medication, sex life, work, social activity and psychological well-being. GERD patients were invited to complete the GERD-QOL, a visual analogue scale (VAS) and a validated Chinese generic QoL (SF-36) questionnaire before and after esomeprazole treatment. Factor analysis was performed for item selection and psychometric properties were measured. An English version was developed by a forward-backward translation process. RESULTS: A final 16-item GERD-QOL questionnaire was developed. The items were grouped into four subscales (Daily activity, Treatment effect, Diet, and Psychological well-being) after factor analysis. GERD-QOL had good item-internal consistency (Cronbach's alpha: 0.64-0.88), high test-retest reliability (intraclass correlation coefficient: 0.73-0.94, P < 0.001). Its subscale scores were correlated with SF-36 and VAS, which demonstrated high construct validity (P < 0.001). Discriminant validity was verified by correlating GERD-QOL scores with symptom severity (P < 0.001). Responsiveness after esomeprazole treatment was significant (paired-t-test P < 0.001). An English version of GERD-QOL was developed. CONCLUSION: The instrument, GERD-QOL, is valid and reliable.