Emphysema due to cigarette smoking is characterized by a loss of alveolar structures. We hypothesize that the disappearance of alveoli involves apoptosis of septal endothelial cells and a decreased expression of lung vascular endothelial growth factor (VEGF) and its receptor 2 (VEGF R2). By terminal transferase dUTP nick end labeling (TUNEL) in combination with immunohistochemistry, we found that the number of TUNEL + septal epithelial and endothelial cells/lung tissue nucleic acid ( μ g) was increased in the alveolar septa of emphysema lungs (14.2 ± 2.0/ μ g, n = 6) when compared with normal lungs (6.8 ± 1.3/ μ g, n = 7) (p < 0.01) and with primary pulmonary hypertensive lungs (2.3 ± 0.8/ μ g, n = 5) (p < 0.001). The cell death events were not significantly different between healthy nonsmoker (7.4 ± 1.9/ μ g) and smoker (5.7 ± 0.7/ μ g) control subjects. The TUNEL results were confirmed by single-stranded DNA and active caspase-3 immunohistochemistry, and by DNA ligation assay. Emphysema lungs (n = 12) had increased levels of oligonucleosomal-length DNA fragmentation when compared with normal lungs (n = 11). VEGF, VEGF R2 protein, and mRNA expression were significantly reduced in emphysema. We propose that epithelial and endothelial alveolar septal death due to a decrease of endothelial cell maintenance factors may be part of the pathogenesis of emphysema.