Background: The impact of transthoracic (TTE) and transhiatal esophagectomy (THE) on long-term health-related quality of life (HR-QoL) in patients with distal esophageal or gastro-esophageal junction (GEJ) cancer has been studied with variable results. This study investigates long-term HR-QoL in patients having undergone TTE or THE. Methods: Disease-free patients after TTE or THE for distal esophageal or GEJ cancer with a follow-up > 2 years were included. Patients who visited the outpatient clinic of a tertiary referral center between 2014 and 2018 were asked to complete EORTC-QLQ-C30 and EORTC-QLQ-OG25 questionnaires. Uni- and multivariable linear regression analysis of HR-QoL was performed in all patients and in subgroups of minimally invasive esophagectomy and neoadjuvant therapy. Results: A total of 132 patients after TTE and 56 after THE were included. When compared with the general population, all patients reported worse HR-QoL in ‘role functioning’ and ‘social functioning’ and in a range of disease- and/or treatment-specific symptoms. The only significant difference between TTE and THE was a better HR-QoL score for “hair loss” following TTE (ß = 29.4,95%CI = -49.108 – −9.671, p = 0.016). Subgroup analysis of minimally invasively operated patients showed better scores in “physical functioning” following TTE (ß = 13.8,95%CI = 2.755–24.933, p = 0.030). No significant differences in HR-QoL were found between TTE and THE after neoadjuvant therapy. Conclusion: Long-term HR-QoL is largely comparable in disease-free patients following TTE or THE for distal esophageal or GEJ cancer. If there were differences between the surgical groups, they were in favor of TTE. These findings may aid in preoperative counseling of patients with esophageal or GEJ cancer.