Hypoxia-inducible factor 1 alpha (HIP-1 alpha) is an oxygen-sensitive subunit of HIP-1, the master transcription factor for cellular response to hypoxia. Down-regulation of the mitochondrial enzyme superoxide dismutase 2 (SOD2) contributes to the stabilization of HIF-1 alpha under hypoxia due to the decreased dismutation of superoxide radical. Here we report that HIF-1 alpha could also regulate the expression of SOD2. We found that both stabilization of HIF-1 alpha expression under nomoxia caused by pVHL deficiency and hypoxia treatment significantly reduced SOD2 expression, and shRNAs specifically against HIF-1 alpha restored SOD2 expression in both circumstances. Further analyses with luciferase reporter assay and chromatin immunoprecipitation assay revealed that HIP-1 alpha inhibited and directly bound to the hypoxia-responsive element in SOD2 promoter. These findings indicated the existence of a positive feedback between HIP-1 alpha and SOD2 and provided new clues for understanding the molecular mechanisms of hypoxia adaptation. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.