Objective To evaluate the clinical outcomes of harmonic scalpel in subxiphoid and subcostal arch approach for resection of anterior mediastinal lesion. Methods We retrospectively analyzed the clinical data of 217 patients with anterior mediastinal lesion at the Department of Thoracic Surgery of Tangdu Hospital of the Fourth Military Medical University from June 2015 to June 2017, among whom 162 underwent thoracoscopic surgery via subxiphoid and subcostal arch approach with harmonic scalpel (a harmonic scalpel group, 95 males and 67 females at an average age of 46.2±18.7 years ranging from 22 to 72 years) and 55 with Ligasure (a Ligasure group, 29 males and 26 females at an average age of 47.7±12.9 years ranging from 31 to 68 years). Operation time, intraoperative blood loss, intraoperative conversion rate, postoperative hospital stay, patients satisfaction score, patients pain score and postoperative complications were compared between both groups. Results All operations were accomplished successfully, and there was no death or conversion to thoracotomy. There was a statistical difference in operation time (58.6±34.8 min vs. 72.8±32.6 min, P=0.01), and intraoperative blood loss (36.2±18.7 ml vs. 41.9±12.9 ml, P=0.04). There was no statistical difference between the two groups in length of hospital stay (4.2±2.6 d vs. 4.5±1.9 d, P=0.36), pain score at postoperative day 1, 3 and 30 (8.3±0.9 vs. 8.5±0.6, P=0.13; 6.4±1.5 vs. 6.9±1.1, P=0.19; 1.3±0.7 vs. 1.4±0.9, P=0.40), patients’ satisfaction score (8.6±1.2 vs. 8.4±1.7, P=0.34), or incidence of postoperative complications (5.6% vs. 9.1%, P=0.35). Conclusion Harmonic scalpel plays an important role in resection of anterior mediastinal lesion via subxiphoid and subcostal arch approach. All tissues are separated and blood vessels are dissected only by the harmonic scalpel, so it is very important for us to handle the harmonic scalpel skillfully.