Abstract Background Anastomotic leak in cervical anastomosis after esophagectomy has consistently been a serious problem. Esophagram has long been utilized to make sure the integrity of anastomosis before starting oral diet. However, the diagnostic accuracy is limited. Drin fluid amylase collected from the cervical anastomotic site is another useful method for its conveniency in specimen collection and the numerical value. But the clinical interpretation varied. The aim of the study was to share the experience in our facility regarding the diagnostic value of esophagram and drain fluid amylase exam. Methods A total of 116 patients with esophageal cancer were reviewed. All patients received open or minimally invasive Mckeown esophagectomy with cervical anastomosis, with or without a neoadjuvant chemoradiotherapy. For the prediction of leak, esophagram and drain fluid amylase were utilized. Esophagram was arranged on the 7th post operative day. And drain fluid amylase was collected twice on the 3rd and the 7th post operative day. We assumed that presence of an elevating trend of the drain fluid amylase level, and the amylase level on the 7th post operative day being more than 80 IU/L, would suggest an anastomotic leak. Results For the entire cohort, the leakage rate was 18.9% (22/116). 67 patients and 48 patients received esophagram exam and drain fluid amylase testing, respectively. The sensitivity and specificity for esophagram were 28.6% and 95%, respectively. The positive and negative predictive values were 40% and 91.9%, respectively. The diagnostic accuracy was 88.1%. The diagnostic value of testing drain fluid amylase by using our criteria yielded a sensitivity and specificity of 75% and 95%, respectively. The positive and negative predictive values were 75% and 95%, respectively. The diagnostic accuracy was 91.7%. Conclusion Comparing with esophagram, testing the drain fluid amylase provided an easier and more accurate way to predict the possible anastomotic leak. The criteria for prediction of leak by using drain fluid amylase were presence of an elevating trend (amylase on POD7 / POD3 >1) and the amylase level on the 7th post operative day being more than 80 IU/L.