Hypoxia inducible factor (HIF)-1 and HIF-2 are transcription factors that mediate the cellular response to hypoxia. Although HIF-1 and HIF-2 share the same target genes, both proteins activate a distinct subset of genes. To identify the target genes preferentially activated by HIF-2 in endothelial cells, DNA microarray analysis was performed to human umbilical vein endothelial cells (HUVECs) with forced expression of either HIF-1α or HIF-2α. In the present study, which is the first comparative study of target genes induced by either HIF-1 or HIF-2 in HUVECs, HIF-1 (and not HIF-2) stimulated mainly glycolytic, hexose metabolic and alcohol metabolic gene expression. However, HIF-2 (but not HIF-1) induced developmental gene expressions such as Fms-like tyrosine kinase 1 (Flt-1) and angiopoietin 2 (Angpt2). Furthermore, CD82 was up-regulated by HIF-2, but not by HIF-1, in response to hypoxia. HIF-2 regulated CD82 gene expression by binding to its HRE consensus sequence located within its first intron. Assessing the function of CD82 in HUVECs forced its expression. This result revealed that CD82 negatively regulates the HUVECs cell migration. The induction of CD82 gene expression in endothelial cells provided new insights into a specific function of HIF-2.