HIF-1a-dependent hypoxic upregulation of PHD2 and PHD3 mRNA and protein levels have been shown in a broad panel of established cancer cell lines. Because oxygen is essential for PHD activity, the feedback increase in PHD protein abundance under hypoxic conditions has been suggested to play a role during reoxygenation, when it might expedite the termination of the HIF response. However, in a time-course spanning a period of ten days, HIF-1 dependent hypoxic upregulation of PHD2 and PHD3 expression peaked after a period of 64–112 hours, but remained markedly upregulated for the duration of the experiment. Furthermore, PHD-abundance and oxygen concentration were titered simultaneously and in vivo and in vitro HIF-1a stability assays were performed. Interestingly, both PHD isoforms retained functional activity even under oxygen concentrations as low as 0.2%O₂. Increased amounts of PHD enzymes were able to de-stabilize HIF-1a-ODD more efficiently even at low oxygen partial pressures. Thus, we suggest a model where HIF-dependent regulation of PHD levels might lead to the adaptation of the PHD-HIF oxygen sensing system to a given tissue pO₂, rather than simply accelerating HIF-1a-destruction during reoxygenation. Such a self-regulatory loop might define a tissue-specific threshold for HIF-1a-activation as a function of local oxygen tension.