In hypoxia, mitochondria-generated reactive oxygen species (ROS) not only stimulate accumulation of the transcriptional regulator of hypoxic gene expression, Hif-1, but also cause oxidative base modifications in hypoxic response elements (HREs) of hypoxia-inducible genes. When the hypoxia-induced base modifications are suppressed, Hif-1 fails to associate with the HRE of the VEGF promoter and VEGF mRNA accumulation is blunted. The mechanism linking base modifications to transcription is unknown. Here we determined if recruitment of base excision DNA repair (BER) enzymes in response to hypoxia-induced promoter modifications was required for transcription complex assembly and VEGF mRNA expression. Using ChIP analyses in pulmonary artery endothelial cells, we found that hypoxia-mediated formation of the base oxidation product 8-oxoguanine (8-oxoG) in VEGF HREs was temporally associated with binding of Hif-1α and the BER enzymes Ogg1 and Ref-1/Ape1 and introduction of DNA strand breaks. Hif-1α co-localized with HRE sequences harboring Ref-1/Ape1 but not Ogg1. Inhibition of BER by siRNA-mediated reduction in Ogg1 augmented hypoxia-induced 8-oxoG accumulation and attenuated Hif-1α and Ref-1/Ape1 binding to the VEGF HRE sequences and blunted VEGF mRNA expression. ChIP-seq analysis of 8-oxoG distribution in hypoxic PAECs showed that most of the oxidized base was localized to promoters with virtually no overlap between normoxic and hypoxic data sets. Transcription of genes whose promoters lost 8-oxoG during hypoxia was reduced, while those gaining 8-oxoG was elevated. Collectively, these findings suggest that the BER pathway links hypoxia-induced introduction of oxidative DNA modifications in promoters of hypoxia-inducible genes to transcriptional activation.