Abstract Background Gastroesophageal reflux disease (GERD) has become a major health problem globally, affecting patients’ health-related quality of life (HRQOL). Barrett’s esophagus (BE) is a precancerous lesion associated with GERD. BE patients might not only suffer from HRQOL losses by GERD but also face psychological distress due to the increased risk of developing cancer. However, the majority of patients in Asia have shorter BE segment which is different from the West. This study aimed to determine whether the HRQOL in BE patients were worse than in healthy referents in Taiwan. Methods Patients who received referral esophagogastroduodenoscopy for various symptoms were evaluated for the existence of BE. Lesions were judged as endoscopically suspected esophageal metaplasia (ESEM) if they showed morphological resemblances to BE by endoscopy. The diagnosis of BE was confirmed by histology with intestinal metaplasia or gastric metaplasia based on the Montreal definition. The World Health Organization Quality of Life (WHOQOL-BREF) was administered to BE patients before treatment. For each BE patient, we selected 2 age-, sex-, educational background and municipality-matched healthy referents, sampled by simple randomization method from a national survey in Taiwan. Multiple linear regression models were constructed to control the potential confounders. Results A total of 84 patients diagnosed with BE were enrolled as BE group and then compared with 168 healthy referents. The BE group had significantly lower WHOQOL-BREF scores than those of healthy referents in the physical domain ( P