Anastomotic leaks after esophagectomy are a significant cause of postoperative morbidity and death. Barium esophagram and esophagogastroduodenoscopy are commonly used to survey for leaks; however, each has inherent risks and limitations. We sought to evaluate the effectiveness of daily drain amylase levels in detecting anastomotic leaks after esophagectomy. We retrospectively reviewed 146 consecutive patients who underwent esophagectomy with cervical and intrathoracic anastomosis using gastric conduit. We collected daily drain amylase levels and obtained postoperative barium esophagrams routinely. Receiver operating characteristic analysis was performed to evaluate the ability of drain amylase to detect anastomotic leaks and to determine the sensitivity and specificity at various cutoff values. There were no in-hospital or outpatient deaths within 30 days of operation in this consecutive series of patients. A leak occurred in 22 of 146 esophagectomy patients (15%) that required postoperative intervention. An additional 13 patients (9%) had a leak requiring only alteration of diet or antibiotics. The sensitivity and specificity for barium esophagram was 36.9% and 95%, respectively. For drain amylase obtained on postoperative day 4, a cutoff of 38 IU/L yielded a sensitivity of 100% and a specificity of 52.0%, and a cutoff of 250 IU/L yielded a sensitivity of 66.7% and a specificity of 95.9% in detecting leaks eventually requiring intervention. Drain amylase levels recorded on day 4 after esophagectomy are more accurate for the detection of esophageal anastomotic leak than barium esophagram. Drain amylase levels represent a noninvasive test that may facilitate safe, early discharge after esophagectomy.