Abstract Objective Anastomotic stricture (AS) is a well described complication after esophagectomy and not only affects nutritional status but also has a detrimental impact on long-term quality of life. This retrospective study explores the incidence of clinically relevant AS in patients undergoing esophagectomy for cancer and investigates the potentially reversible factors associated with AS. Methods A prospectively entered clinical database of consecutive patients undergoing esophagectomy at a high-volume referral center over a decade (1/2013-12/2022) was queried for the presence of post-operative clinically significant AS, defined as stricture requiring endoscopic dilation. Multiple variables encompassing patient-related risk factors, tumor pathology, prior treatment, operative factors, and post-op complications were included in logistic regression analyses to delineate predictors of stricture formation. Results Of 1015 patients in the database, 115 (11.3%) developed AS requiring at least 1 post-op dilation. Although higher American Society of Anesthesiologists (ASA) grading was associated with elevated AS rate impact with most patients being ASA 2 and 3; 24% and 49% respectfully (p < 0.05). Specific patient factors/comorbidities such as age, peripheral or coronary vascular disease, and diabetes mellitus did not emerge as significant predictors. Surprisingly, neither histology, nor neoadjuvant therapy (chemo or chemoradiation) were associated with AS. Both a cervical anastomosis and a intra-operative pyloromyotomy had a higher AS rate than an intra-thoracic anastomosis (OR 13.3, p=0.006) and patients without a myotomy (p=<0.006). Other operative factors including approach (open vs MIE) conduit type (stomach/jejunum/colon) or width (3/4/5/6 cm) did not impact AS rate. All patients had a hand-sewn anastomosis. No post-operative outcome measures (e.g. leak, epidural use, hypotension) was associated with the development of AS. Conclusion Our results highlight the interplay of patient-related risk factors, tumor pathology, prior treatment, and operative factors in the development of post esophagectomy strictures. Understanding these predictors could potentially influence risk stratification and may facilitate tailored postoperative care strategies for improved patient outcomes.