We have attempted to identify a biologic rationale for the local aggressiveness and late treatment failure of resected non-small cell lung cancer involving the thoracic inlet. Tumor specimens from 28 patients who underwent a new transcervical approach were analyzed for the expression of tumor proliferative activity, suppressor-gene p53, intratumoral and peritumoral blood vessel invasion by tumor cells, the presence and degree of angiogenesis (induction of new capillaries and venules), and other biologic variables. Eighty-nine percent of the neoplasms were moderately or poorly differentiated, 89% expressed either an intermediate or high proliferative activity, 39% showed p53 aberrations, 71% exhibited induction of angiogenesis, and 39% had tumors that were positive for blood vessel invasion. With a median follow-up time of 3.5 years (range, 8 to 145+ months), the overall projected 5-year survival was 29% and the median disease-free interval was 23 months. Results of univariate and multivariate analysis of survival and the disease-free interval identified the degree of angiogenesis (density less than 1 versus more than 1 and number of neovessels less than 6 versus more than 6) as the only independent and significant predictors of the disease-free interval. Patients whose tumor showed a density of angiogenesis of 1 or greater and a number of neovessels of 6 or greater faced a significantly (p = 0.0001) higher relative risk of suffering systemic recurrence of their primary tumor than did their low-risk counterparts. Results demonstrate that angiogenesis significantly correlates with late treatment failure (metastasis), and this is acquired at a critical density and number of vessels.