〔Abstract〕 Objective To investigate the safety and clinical efficacy of video-assisted thoracic surgery via subxiphoid approach (S-VATS) and video-assisted thoracic surgery via lateral intercostal approach (I-VATS) for mediastinal mass resection. Methods A total of 143 patients with mediastinal mass resection admitted to thoracic surgery department of the First Affiliated Hospital of Shenzhen University from January 2017 to November 2021 were retrospectively analyzed. Among them, 128 subjects who met the inclusion and exclusion criteria of this study were divided into an observation group and a control group according to the observational research method. 53 cases in the observation group were treated with S-VATS to remove mediastinal masses, while 75 cases in the control group were treated with I-VATS to remove mediastinal masses. Comparison the differences of the two groups of patients with clinical characteristics, surgical index (operative time and intraoperative blood loss), and clinical observation index after surgery [drainage tube indwelling time after surgery, the chest of flow rate, length of hospital stay, postoperative 24 h pain score, whether into the intensive care unit (ICU), the differences between the complications and hospitalization expenses]. Results There were statistically significant differences in age and pathological types between the two groups (P < 0.05). There was no significant difference in height, body weight, body mass index (BMI), gender, smoking history, diabetes history, myasthenia gravis history and hypertension history between the two groups (P > 0.05). There was no significant difference in operation time, intraoperative blood loss, postoperative drainage tube indwelling time, postoperative thoracic drainage volume, postoperative hospital stay and postoperative complications between the two groups (P > 0.05). The 24 h postoperative pain score and hospitalization cost of the observation group were lower than those of the control group, and the differences were statistically significant (P < 0.05). Conclusion Compared with I-VATS, S-VATS has better surgical field and safety in the resection of mediastinal masses. S-VATS has advantages in surgical incision pain and hospitalization cost, which is more conducive to promote the rapid recovery of patients after surgery and improve the short-term quality of life of patients.