Objective To explore the minimal invasiveness and practability of combined video-assisted thoracic surgery (VATS) with two trocars and endoscopic ultrasonography (EUS) in the treatment of esophageal leiomyoma. Methods Between February 2007 and February 2012, we retrospectively analysed the clinical data of 166 patients who underwent various surgeries for the treatment of esophageal leiomyoma. Among them, 62 received routine thoracotomy (group A), 49 accepted conventional VATS surgery with three trocars (group B), and 55 underwent combined VATS surgery with two trocars and EUS (group C). Then, we summarized the clinical indexes of patients in all the three groups for further comparative analysis. Results There was no significant difference among the three groups in age, gender, and lesion location, origin level and size (P > 0.05). There were significant differences between group A and C in blood loss, surgery time, intraoperative localization, postoperative incision pain, hospitalization expenses, length of hospital stay, fasting time, pulmonary infection, and the complications during the follow-up (P < 0.05). There were significant differences between group C and B in blood loss, surgery time, intraoperative localization, fasting time and pulmonary infection (P < 0.05). Conclusion Combined VATS surgery with two trocars and EUS is safe, minimally invasive, thorough with few complications, which is worthy of clinical promotion.