Background Anastomotic leakage is associated with increased morbidity and mortality after esophagectomy. Calcification of the arteries supplying the gastric tube has been identified as a risk factor for leakage of the cervical anastomosis, but its potential contribution to the risk of intrathoracic anastomotic leakage has not been elucidated. This study evaluated the relationship between calcification and the occurrence of leakage of the intrathoracic anastomosis after Ivor-Lewis esophagectomy. Methods Consecutive patients who underwent minimally invasive esophagectomy for cancer at 2 institutions were analyzed. Diagnostic computed tomography images were used to detect calcification of the arteries supplying the gastric tube (eg, aorta, celiac axis). Multivariable logistic regression analysis was used to determine the relationship between vascular calcification and anastomotic leakage. Results Of 167 included patients, anastomotic leakage occurred in 40 (24%). In univariable analysis, leakage was most frequently observed in patients with calcification of the aorta (major calcification: 37% leakage 16 of 43; minor calcification: 32% 18 of 56; no calcification: 9% 6 of 70, p < 0.001). Calcification of other studied arteries was not significantly associated with leakage. A significant association with leakage remained for minor (odds ratio, 5.4; 95% confidence interval, 1.7 to 16.5) and major (odds ratio, 7.0; 95% confidence interval, 1.9 to 26.4) aortic calcifications in multivariable analysis. Conclusions Atherosclerotic calcification of the aorta is an independent risk factor for leakage of the intrathoracic anastomosis after Ivor-Lewis esophagectomy for cancer. The calcification scoring system may aid in patient selection and lead to earlier diagnosis of this potentially fatal complication.