Abstract Background There is little information of the validity of generic instruments in measuring health-related quality of life (HRQOL) in patients with dyspepsia. We aimed to assess the reliability and validity of the EQ-5D, a brief and simple instrument, in measuring HRQOL in adult patients with dyspepsia. Methods Consecutive adults with dyspepsia attending the Gastroenterology clinic in a tertiary referral center were interviewed with the EQ-5D (both English and Malay versions), the short-form Nepean Dyspepsia Index (SF-NDI), the SF-36 and Leeds Dyspepsia Questionnaire (LDQ). Known-groups and convergent construct validity were investigated by testing hypotheses at attribute and overall levels. A repeat telephone interview was conducted 2 weeks later to assess test-retest reliability. Results A total of 113 patients (mean (SD) age: 53.7 (14) years; 49.5% male; 24.8% Malays, 37.2% Chinese; 70.8% functional dyspepsia) were recruited. Response rate was 100% with nil missing data. Known-groups validation revealed 20/26 hypotheses fulfillment. Patients with more severe dyspepsia reported more problems with their usual activity (p = 0.07) and pain (p = 0.06) and demonstrated lower median VAS scores (60 vs 70, p = 0.002) and EQ-5D utility scores (0.72 vs 0.78, p = 0.002). Those reporting problems in various EQ-5D dimensions had significantly lower scores in relevant SF-36 and SF-NDI dimensions. The overall EQ-5D utility score also demonstrated good correlation with the SF-36 summary physical and mental scores and the SF-NDI total score. Intraclass correlation coefficient for test-retest reliability was 0.66 (95% CI = 0.55 – 0.76). Conclusion The EQ-5D is an acceptable, valid and reliable generic instrument for measuring HRQOL in adult patients with dyspepsia.