BACKGROUND: Extrapleural pneumonectomy for malignant pleural mesothelioma is considered an aggressive procedure, but symptomatic and quality of life changes are unknown. METHODS: Between 1997 and 2004, 16 consecutive patients underwent extrapleural pneumonectomy for mesothelioma followed by chemo-radiotherapy. Tumor-related symptoms and quality of life (Short-Form-36 and St. George's questionnaires) were assessed pre, 3, 6, 12, and 24 months postoperatively. RESULTS: Thirty-day postoperative major morbidity was 31% with no mortality. At 3 months postoperatively, dyspnea improved in 10 patients (62%), pain in 12 (75%), cough in 10 (62%), fever in 11 (68%), Karnofsky-index in 10 (62%), Short-Form-36 physical-component-summary in 8, mental-component-summary in 5 and total St. George score in 8 (50%). At 1 year 10 (62%) patients were alive and majority of improved parameters were still stable. Thereafter they usually started to decline. Survival was influenced by nonepithelial histology (P < 0.01) and N2-disease (P < 0.01), which showed to be the only prognosticator at Cox regression (P < 0.0001, Odd ratio 5.4). Among symptomatic variables, a 3-month postoperative Short-Form-36 physical-component-summary above the median value correlated significantly with a better prognosis (P < 0.02). CONCLUSIONS: Extrapleural pneumonectomy may rapidly improve symptoms as well as quality of life, especially in physical domains. Other than biological factors, postoperative Short-Form-36 physical component as well, significantly influenced the prognosis.