Introduction: The primary objective of the present systematic review was to evaluate the safety and efficacy of extrapleural pneumonectomy (EPP) for patients with malignant pleural mesothelioma. Methods: A systematic review of relevant studies identified through five online search databases was performed. Two reviewers independently appraised each study. Results: Thirty-four of 58 relevant studies from 26 institutions containing the most updated data were evaluated for survival and perioperative outcomes after EPP. The median overall survival varied from 9.4 to 27.5 months, and 1-, 2-, and 5-year survival rates ranged from 36 to 83%, 5 to 59%, and 0 to 24%, respectively. Overall perioperative mortality rates ranged from 0 to 11.8%, and the perioperative morbidity rates ranged from 22 to 82%. Quality of life assessments from three studies reported improvements in nearly all domains at 3 months postoperatively. Patients who underwent trimodality therapy involving EPP and adjuvant chemoradiotherapy had a median overall survival of 13 to 23.9 months. Discussions: The current evidence suggests that selected patients with malignant pleural mesothelioma may benefit from EPP, especially when combined with neoadjuvant or adjuvant chemotherapy and adjuvant radiotherapy.