Malignant pleural mesothelioma is usually a fatal cancer for which operation has been the mainstay of treatment because chemotherapy and radiation are relatively ineffective. The choice of operation for malignant pleural mesothelioma remains controversial. Extrapleural pneumonectomy has been advocated because it allows complete removal of gross tumor and can be associated with long-term survival. To evaluate extrapleural pneumonectomy, we conducted a prospective multiinstitutional trial in patients with biopsy-proved previously untreated malignant pleural mesothelioma. Criteria for extrapleural pneumonectomy were (1) potentially completely resectable unilateral disease by computed tomography scan, (2) predicted postresection forced expiratory volume in 1 second greater than 1 L/sec, and (3) no other major medical problems. Patients who were not candidates for extrapleural pneumonectomy had a more limited operation with or without adjuvant therapy or had nonsurgical treatment. From September 1985 to June 1988 83 eligible patients (64 male, 19 female) were entered. The mean age for all patients was 59.7 years. Only 20 of the 83 patients (24%) underwent extrapleural pneumonectomy. Three of these 20 patients (15%) died postoperatively. The recurrence-free survival was significantly longer for the patients undergoing extrapleural pneumonectomy than for the other two groups (p = 0.03), but there was no difference in overall survival among the three groups. In univariate analyses, epithelial versus sarcomatoid and mixed histologic findings and platelet count less than 400,000 were associated with a better overall survival (p = 0.02), and performance status (Karnofsky less than 80) was predictive of recurrence (p = 0.02). In a multivariate analysis, histologic findings, sex, age, extrapleural pneumonectomy, weight loss, and performance status all had no significant impact on survival. Extrapleural pneumonectomy was associated with a greater likelihood of relapse in distant sites than were limited operation and nonsurgical treatment. We conclude that (1) only a small proportion of all patients with malignant pleural mesothelioma are candidates for extrapleural pneumonectomy, (2) extrapleural pneumonectomy carries a significant operative mortality and does not seem to improve overall survival compared with more conservative forms of treatment, (3) extrapleural pneumonectomy alters the patterns of relapse, and (4) factors previously thought to have an impact on survival in other series did not affect outcome in this trial.