Background: There has been an evolving role of surgery for malignant pleural mesothelioma (MPM) over the past 25 years. The objective of this study was to investigate whether the survival results for MPM patients after surgery have improved within this time period by an analysis of a prospective cohort of 540 patients. Methods: Five hundred and forty consecutive patients with MPM were treated by a thoracic surgical team. These patients were categorized into two groups: Group I (before September1999, n = 270) and Group II (after September 1999, n = 270). The two groups were compared for clinic opathologic data and survival results. The statistical analyses of all prognostic parameters used overall survival as the end point. Results: Group II had higher proportions of epithelial tumors and patients who had preoperative PET scan, extrapleural pneumonectomy (EPP), postoperative radiotherapy and pemetrexed chemotherapy. The overall survival results were significantly better in Group II compared with Group I (p = 0.004). Four factors were found to be independently associated with an improved survival in multivariate analysis: epithelial subtype (p <0.001); surgeon's experience with >100 cases (p = 0.006), patients who underwent EPP (p = 0.001) and those who received pemetrexed chemotherapy (p = 0.016). The median survival for patients selected for EPP was 20 months, as compared to 9 months for pleurodesis/decortication and pleurodesis. Conclusions: Significant improvement of overall survival results has been achieved in the more recent 270 MPM patients through accumulated experience in a specialist treatment center.