Hypoxia-inducible factor-1α (HIF-1α) transactivates genes required for energy metabolism and tissue perfusion and is necessary for embryonic development and tumor explant growth. HIF-1α is overexpressed during carcinogenesis, myocardial infarction, and wound healing; however, the biological consequences of HIF-1α overexpression are unknown. Here, transgenic mice expressing constitutively active HIF-1α in epidermis displayed a 66% increase in dermal capillaries, a 13-fold elevation of total vascular endothelial growth factor (VEGF) expression, and a six- to ninefold induction of each VEGF isoform. Despite marked induction of hypervascularity, HIF-1α did not induce edema, inflammation, or vascular leakage, phenotypes developing in transgenic mice overexpressing VEGF cDNA in skin. Remarkably, blood vessel leakage resistance induced by HIF-1α overexpression was not caused by up-regulation of angiopoietin-1 or angiopoietin-2. Hypervascularity induced by HIF-1α could improve therapy of tissue ischemia.