Angiogenesis, the formation of new vessels, has been demonstrated to be a potent and independent indicator of prognosis in non-small cell lung cancer patients. The extent of differentiation of the tumor vessels may affect access of peripheral white cells and egress or invasion of tumor cells. This has not been assessed in relation to tumor microvessel density or other variables and may be a marker of vascular remodeling. LH39 is a monoclonal antibody recognizing an epitope located at the lamina lucida of mature small veins and capillaries but not in newly formed vessels. We examined the ratio of mature:immature vessels in 81 non-small cell lung carcinomas and correlated the vascular maturation index (VMI) to different clinicopathological variables including angiogenesis. Mature vessels were defined by staining with antibodies to both LH39 and to CD31, using double immunohistochemistry, whereas immature vessels stained only for CD31. VMI was defined as the percentage fraction of mature vessels (LH39 positive)/total number of vessels (CD31 positive). The median VMI in lung carcinomas was 46% (range, 15-90%). There was a significant inverse correlation between high VMI and low thymidine phosphorylase expression (P = 0.0001), high VMI and nuclear p53 negativity (P = 0.01), high VMI and low angiogenesis (P = 0.0001), as well as between high VMI and absence of nodal involvement (P = 0.01). Low angiogenesis and high VMI were associated with a significantly better outcome (P = 0.0001 and P = 0.02, respectively). These findings show that there is a wide variation in the differentiation of tumor vasculature in lung carcinomas, and VMI gives new information on the degree of active tumor vascular remodeling independently from microvessel quantitation.