BACKGROUND: Higher operative risks after pneumonectomy for non-small cell lung cancer (NSCLC) have been reported after neoadjuvant chemotherapy or radiotherapy, or both. Patients who underwent pneumonectomy for NSCLC were evaluated for effect of neoadjuvant treatment on mortality and morbidity, especially bronchopleural fistula. METHODS: Between 1996 and 2003, 130 consecutive patients underwent pneumonectomy: 35 received preoperative radiotherapy and chemotherapy (the neoadjuvant group), and 95 patients did not (the first-surgery group). Operative mortality and postoperative complications were compared between the groups. RESULTS: Minor postoperative complications were comparable in both groups (p > 0.10). Five patients in the neoadjuvant group and 10 in the first-surgery group had serious complications (p = 0.55). Eight had bronchopleural fistulas (7 right and 1 left, p < 0.01); 3 were in the neoadjuvant group (p = 0.49). Three fistulas required reoperation. One patient in the first-surgery group died within 30 days postoperatively. Duration of symptoms (hazard ratio, 6.6; p = 0.01) and right-sided pneumonectomy (hazard ratio, 2.4; p = 0.05) were associated with an increased risk of bronchopleural fistula. Induction treatment, postoperative radiotherapy, or coverage of the bronchial stump did not increase the risk of bronchopleural fistulation. Survival at 1 and 5 years was comparable for the neoadjuvant and first-surgery groups: 74% and 46% vs 72% and 34%, respectively (p > 0.2). CONCLUSIONS: Pneumonectomy is a safe procedure with low operative mortality. Postoperative morbidity is significant, especially bronchopleural fistulas after right-sided pneumonectomy (11%). However, neither operative mortality nor morbidity appears to be directly associated with preoperative radiotherapy or chemotherapy.