The SIN3A-HDAC complex is a master transcriptional repressor, required for development but often deregulated in disease. Here, we report that the recently identified new component of this complex, SINHCAF/FAM60A, links the SIN3A-HDAC co-repressor complex function to the hypoxia response. We show that SINHCAF specifically repress HIF 2α mRNA and protein expression, via its interaction with the transcription factor SP1, and recruitment of HDAC1 to the HIF 2α promoter. SINHCAF control over HIF 2α results in functional cellular changes in in vitro angiogenesis, and viability. Our analysis reveals an unexpected link between SINHCAF and the regulation of the hypoxia response.