Background: Surgical treatment of T4 non-small cell lung cancer (NSCLC) patients with mediastinal involvement is controversial. This study was conducted to propose subgroups of patients with T4 NSCLC with mediastinal involvement who are more likely to benefit from resection. Methods: Consecutive patients with T4 NSCLC with mediastinal involvement who underwent thoracotomy (n = 146) were retrospectively analyzed. Actuarial survival was calculated. Factors associated with overall survival were identified. Results: Four operative deaths occurred in pneumonectomy patients. The overall 5-year survival rate was 22.7%; median survival was 24.8 months. Factors favoring survival included complete resection (p < 0.001), N2-negative disease (p < 0.001), and pulmonary great vessel invasion (p < 0.001). Multivariate analysis of 131 patients undergoing lung resection found three factors associated with increased survival: pulmonary great vessel involvement (relative risk [RR] of death, 0.365; 95% confidence interval [CI], 0.208 to 0.639; p < 0.001), R0 resection (RR, 0.387; 95% CI, 0.209 to 0.714; p = 0.002), and postoperative chemotherapy (RR, 0.255; 95% CI, 0.134 to 0.487; p < 0.001). Male sex (RR, 2.962; 95% CI, 1.479 to 5.934; p = 0.002) and N2-positive disease (RR, 3.220; 95% CI, 1.640 to 6.323; p < 0.001) were associated with decreased survival. Conclusions: N2-positive, T4 NSCLC with mediastinal involvement is not suitable for resection. T4 NSCLC patients with pulmonary great vessel involvement had better survival rates than other T4 subgroups. Pneumonectomy should be done with caution due to a high mortality risk and poor prognosis. Further studies are warranted to assess the role of sex on survival. © 2009 The Society of Thoracic Surgeons.