Objective To explore the feasibility and clinical effect of subxiphoid uniportal video-assisted thoracoscopic surgery in the treatment of the anterior mediastinal tumors. Methods The clinical data of 38 patients, who underwent subxiphoid uniportal video-assisted thoracoscopic surgery for anterior mediastinal tumor in Shanghai Pulmonary Hospital of Tongji University from Oct. 2014 to Aug. 2018, were retrospectively analyzed. Among them, 20 were males and 18 were females, the average age was (57.8±14.8) years, and the average diameter of anterior mediastinal tumors was (2.8±1.7) cm. The surgery was performed under video-assisted thoracoscope through an about 4 cm subxiphoid longitudinal incision. Results All the 38 cases of subxiphoid uniportal video-assisted thoracoscopic surgery were performed successfully without conversion to thoracotomy or perioperative death. Except for one patient who received mechanical ventilatory support for 1 week because of worsened myasthenia gravis symptoms, there were no other complications. The operative time, volume of bleeding, volume of drainage on the operation day and hospital stay after surgery were 1-4 (1.9±0.8) h, 10-400 (87.5±68.7) mL, 50-650 (237.4±176.4) mL and 1-19 (4.1±2.9) d, respectively. Postoperative pathology showed 1 case of type A thymoma, 1 case of type B2 thymoma, 1 case of type B3 thymoma, 5 cases of type AB thymoma, 1 case of thymic squamous carcinoma, 6 cases of thymic hyperplasia, 16 cases of thymic cyst, 6 cases of simple thymus and fat and 1 case of bronchial cyst. The visual analogue scale scores on 1, 3 and 6 months after surgery were 3.8±2.2, 1.5±1.4 and 0.8±0.6, respectively. Conclusion Subxiphoid uniportal video-assisted thoracoscopic surgery is a safe, efficient, satisfactory procedure for early stage thymoma, benign anterior mediastinal tumors and some early stage anterior mediastinal malignant tumors, and it can effectively avert the intractable incision pain caused by intercostal nerve injury.