Background: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard of care for patients with esophageal or junctional cancer, but the long-term impact of nCRT on health-related quality of life (HRQOL) is unknown. The purpose of this study is to compare very long-term HRQOL in long-term survivors of esophageal cancer who received nCRT plus surgery or surgery alone. Patients and methods: Patients were randomly assigned to receive nCRT (carboplatin/paclitaxel with 41.4-Gy radiotherapy) plus surgery or surgery alone. HRQOL was measured using EORTC-QLQ-C30, EORTC-QLQ-OES24 and K-BILD questionnaires after a minimum follow-up of 6 years. To allow for examination over time, EORTC-QLQ-C30 and QLQ-OES24 questionnaire scores were compared with pretreatment and 12 months postoperative questionnaire scores. Physical functioning (QLQ-C30), eating problems (QLQ-OES24) and respiratory problems (K-BILD) were predefined primary end points. Predefined secondary end points were global quality of life and fatigue (both QLQ-C30). Results: After a median follow-up of 105 months, 123/368 included patients (33%) were still alive (70 nCRT plus surgery, 53 surgery alone). No statistically significant or clinically relevant differential effects in HRQOL end points were found between both groups. Compared with 1-year postoperative levels, eating problems, physical functioning, global quality of life and fatigue remained at the same level in both groups. Compared with pretreatment levels, eating problems had improved (Cohen's d-0.37, P=0.011) during long-term follow-up, whereas physical functioning and fatigue were not restored to pretreatment levels in both groups (Cohen's d-0.56 and 0.51, respectively, both P<0.001). Conclusions: Although physical functioning and fatigue remain reduced after long-term follow-up, no adverse impact of nCRT is apparent on long-term HRQOL compared with patients who were treated with surgery alone. In addition to the earlier reported improvement in survival and the absence of impact on short-term HRQOL, these results support the view that nCRT according to CROSS can be considered as a standard of care. Trial registration number: Netherlands Trial Register NTR487.