OBJECTIVE: The authors examine the feasibility and efficacy of trimodality therapy in the treatment of malignant pleural mesothelioma and identify prognostic factors. BACKGROUND: Mesothelioma is a rare, uniformly fatal disease that has increased in incidence in recent decades. Single and bimodality therapies do not improve survival. METHODS: From 1980 to 1995, 120 patients underwent treatment for pathologically confirmed malignant mesothelioma at Brigham and Women's Hospital and Dana-Farber Cancer Institute (Boston, MA). Initial patient evaluation was performed by a multimodality team. Patients meeting selection criteria and with resectable disease identified by computed tomography scan or magnetic resonance imaging underwent extrapleural pneumonectomy followed by combination chemotherapy and radiotherapy. RESULTS: The cohort included 27 women and 93 men with a mean age of 56 years. Operative mortality rate was 5.0%, with a major morbidity rate of 22%. Overall survival rates were 45% at 2 years and 22% at 5 years. Two and 5-year survival rates were 65% and 27%, respectively, for patients with epithelial cell type, and 20% and 0%, respectively, for patients with sarcomatous or mixed histology tumors. Nodal involvement was a significant negative prognostic factor. Patients who were node negative with epithelial histology had 2- and 5-year survival rates of 74% and 39%, respectively. Involvement of margins at time of resection did not affect survival, except in the case of full-thickness, transdiaphragmatic invasion. Classification on the basis of a revised staging system stratified median survivals, which were 22, 17, and 11 months for stages I, II, and III, respectively (p = 0.04). CONCLUSIONS: Extrapleural pneumonectomy with adjuvant therapy is appropriate treatment for selected patients with malignant mesothelioma selected using a revised staging system.