Objective To assess the outcome of harmonic scalpel (HS) in esophageal cancer surgery and to provide evidence for the role of HS in the enhanced recovery after surgery (ERAS) and short-term prognosis after esophageal cancer surgery. Methods We collected the clinical data of 81 esophageal cancer patients receiving surgery by HS between January 1 and December 31, 2016 and successfully followed up in our department. There were 67 males and 14 females with an average age of 64.07±7.52 years. Sweet approach was adopted in 16 patients, Ivor-Lewis approach in 23 and McKeown approach in 40. Intrathoracic anastomosis was completed in 41 patients and cervical anastomosis in 40. The length of total hospital stay and postoperative hospital stay, operation time, intraoperative blood loss, duration and volume of thoracic drainage and perioperative complications were recorded and compared in patients with different surgical approaches and anastomosis sites. Results For these 81 patients, the operation time was 276.7±70.4 min, and the intraoperative blood loss was 115.9±69.7 ml. The postoperative duration of thoracic drainage, postoperative complication rate and the drainage volume were 12.3±5.3 d, 35.80% and 1 411.9±1 199.5 ml, respectively. During the follow-up, 15 patients died and the cumulative survival rate was 81.48%. There was no obvious HS-related complication. The operation time of Sweet approach was shorter than that of Ivor-Lewis or McKeown approach (P=0.012) and the dissected lymph nodes were less in Sweet approach (P=0.035). There was no significant difference in perioperative indexes and postoperative short-term prognosis between intrathoracic anastomosis and cervical anastomosis. Conclusion HS is widely used in the surgery for esophageal cancer with safety and effectiveness, which is worthy of clinical application.