Abstract Background Transthoracic esophagectomy with either intrathoracic or cervical anastomosis is considered standard of care in patients with mid to distal esophageal or gastroesophageal junction (GEJ) cancer. Patients after esophagectomy will experience a deterioration in health-related quality of life (HR-QoL) after esophageal cancer surgery. Whilst some reports describe long-lasting deterioration, other reports show recovery of HR-QoL comparable with the general population after 2 years. The aim of this study was to investigate the difference in HR-QoL in patients after a transthoracic esophagectomy with either intrathoracic- or cervical anastomosis in a nationwide database. Methods A nationwide cohort study was performed combining data from two registries: Netherlands Cancer Registry (NCR) and Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP). All patients after esophagectomy for mid/distal esophageal or GEJ cancer between 2015 and 2022 were included. HR-QoL was measured at baseline, 3, 6, 9, 12, 18, and 24 months postoperatively using EORTC QLQ-C30 and OG-25 questionnaires. Linear mixed models were used to assess the mean score difference between patients with intrathoracic and cervical anastomosis. A difference of 10 points or more was considered clinically relevant. Adjustments were made for potential confounders (age, gender, ASA classification). Results Of the 4269 registered patients in the NCR, in 1274 patients at least one questionnaire was available. Of these patients 346 underwent an esophagectomy with cervical - and 928 with intrathoracic anastomosis. Patients after esophagectomy with cervical anastomosis reported statistically significant more problems in the following categories: dysphagia, couching, trouble eating with others and swallowing saliva during the first 3 months, choked when swallowing and trouble talking during the first 12 months postoperatively. In all other categories no significant difference was found. Only trouble talking at the 3-month time point was considered as a clinically relevant difference. Conclusion Although the intrathoracic anastomosis is associated with significantly better HR-QoL in several categories, only trouble talking at 3 months postoperatively was considered clinically relevant. Overall HR-QoL was comparable for esophageal cancer patients after an esophagectomy with either a cervical or intrathoracic anastomosis.