The heterodimeric hypoxia-inducible transcription factors (HIFs) are central regulators of the cellular and systemic response to low oxygen partial pressure. HIF-a subunits are constitutively expressed but rapidly degraded under normoxic conditions. Prolyl-4-hydroxylase domain-containing enzymes (PHDs) proteolytically regulate HIF-a by oxygen-dependent hydroxylation. Subsequently, these hydroxylation sites are bound by pVHL which serves as substrate recognition unit of an E3 ligase targeting HIF-a for degradation by the ubiquitin-proteasome pathway. We identified the peptidyl-prolyl cis/trans isomerase FK506-binding protein 38 (FKBP38) as a specific interactor of PHD2. Neither FKBP38 mRNA nor protein levels are regulated under hypoxic conditions or after PHD inhibition, suggesting that FKBP38 is not a HIF/PHD2 target. Stable RNAi-mediated depletion of FKBP38 resulted in increased HIF hydroxylation activity and decreased HIF-dependent reporter gene activity. Downregulation of FKBP38 did not affect PHD2 mRNA levels but increased PHD2 protein levels, leading to enhanced HIF-1a degradation and attenuation of HIF target gene regulation. Increased PHD2 protein levels in FKBP38-depleted cells were due to enhanced PHD2 protein stability, suggesting that FKBP38 is involved in the proteolytic regulation of PHD2.