Background: Anastomotic leak is the most common major complication after esophagectomy. We investigated the 2016 American College of Surgeons National Surgical Quality Improvement Program esophagectomy targeted database to identify risk factors for anastomotic leak.Methods: Patients who underwent esophagectomy for cancer were included. Patients experiencing an anstomotic leak were identified, and univariate and multivariable logistic regression was performed to identify variables independently associated with anastomotic leak.Results: Of 915 patients included, 83% were male and the median age was 64 years.Patients with anastomotic leak more frequently had additional complications (87% vs 36%, P < .001). Rates of reoperation (64% vs 11%, P < .001) and mortality (8% vs 2%, P = .001) were higher in patients with anastomotic leak. After adjusting for patient and procedure characteristics, prolonged operative time (for each additional 30-minutes; adjusted odds ratios (AOR) 1.068, 95% CI, 1.022-1.115, P = .003), increased preoperative WBC count (for each 3000/µL increase; AOR 1.323, 95% CI, 1.048-1.670, P = .019), pre-existing diabetes (AOR 1.601, 95% CI, 1.012-2.534, P = .045), and perioperative transfusion (AOR 1.777, 95% CI, 1.064-2.965, P = .028) were independently associated with anastomotic leak.Conclusion: Both patient and procedure-related factors are associated with anastomotic leak. Though frequently non-modifiable, these findings could facilitate risk stratification and early detection of anastomotic leak to reduce associated morbidity.