Abstract Background The Functional Assessment of Cancer Therapy-Esophageal (FACT-E) is a validated patient-reported outcome instrument that measures four subscales of general cancer health and one subscale specific to esophageal cancer. To make the instrument more clinically useful, therapeutic thresholds known as minimal clinically important differences (MCID) are needed. The purpose of this study was to calculate the MCID for the FACT-E and its subscales for patients undergoing an esophagectomy. Methods The study was based on a retrospective analysis of a registry maintained by a high volume North American tertiary care referral centre, which includes the FACT-E collected between August 2004 and September 2023. The FACT-E was administered at nine time points over the course of a patient’s care, ranging from the time of first presentation to 5 years post-esophagectomy. This study used two distribution-based approaches – the standard error (SE) and the standard deviation (SD) – to calculate the MCID for the FACT-E’s total score and its five subscales. Nonparametric bootstrapping was used to generate 95% confidence intervals for each MCID. Results There were 731 participants included in this study but not all of those completed each subscale at each time point. The MCID for physical well-being ranged from 2.2-3.1 using SE and 2.3-3.4 using SD, from 2.1-3.6 using SE and 2.2-3.6 using SD for social well-being, 1.2-1.7 using SE and from 1.4-2.0 using SD for emotional well-being, 2.1-2.4 using SE and 3.2-3.6 using SD for functional well-being, and from 3.2-4.3 using SE and from 4.3-6.4 using SD for the esophagus cancer subscale. The MCID for the total score ranged from 6.7-8.3 using SE and from 8.9-11.2 using SD. Conclusion The MCID thresholds for the FACT-E subscales vary depending on when they are collected and how they are measured. In general, smaller thresholds of change are needed in the social and emotional well-being subscales, while larger ones are needed for the esophagus cancer subscale. Overall, the MCID for the FACT-E total score ranged from 6 to 11. Clinicians should consider these MCID if using the FACT-E to assess changes in patients’ symptom severity before and after esophagectomy.