Objective: Hypoxia plays a pivotal role in development and progression of restenosis after vascular injury. Under hypoxic conditions the hypoxia-inducible factors (HIFs) are the most important transcription factors for the adaption to reduced oxygen supply. Therefore the aim of the study was to investigate the effect of a local HIF-inhibition and overexpression on atherosclerotic plaque development in a murine vascular injury model. Methods and results: After wire-induced vascular injury in ApoE^-/- mice a transient, local inhibition of HIF as well as an overexpression approach of the different HIF-subunits (HIF-1α, HIF-2α) by adenoviral infection was performed. The local inhibition of the HIF-pathway using a dominant-negative mutant dramatically reduced the extent of neointima formation. The diminished plaque size was associated with decreased expression of the well-known HIF-target genes vascular endothelial growth factor-A (VEGF-A) and its receptors Flt-1 and Flk-1. In contrast, the local overexpression of HIF-1α and HIF-2α further increased the plaque size after wire-induced vascular injury. Conclusions: Local HIF-inhibition decreases and HIF-α overexpression increases the injury induced neointima formation. These findings provide new insight into the pathogenesis of atherosclerosis and may lead to new therapeutic options for the treatment of in stent restenosis.