The hypoxia‐inducible factor (HIF) prolyl‐hydroxylases (human PHD1‐3) catalyze prolyl hydroxylation in oxygen‐dependent degradation (ODD) domains of HIFα isoforms, modifications that signal for HIFα proteasomal degradation in an oxygen‐dependent manner. PHD inhibitors are used for treatment of anemia in kidney disease. Increased erythropoietin (EPO) in patients with familial/idiopathic erythrocytosis and pulmonary hypertension is associated with mutations in EGLN1 (PHD2) and EPAS1 (HIF2α); a drug inhibiting HIF2α activity is used for clear cell renal cell carcinoma (ccRCC) treatment. We report crystal structures of PHD2 complexed with the C‐terminal HIF2α‐ODD in the presence of its 2‐oxoglutarate cosubstrate or N‐oxalylglycine inhibitor. Combined with the reported PHD2.HIFα‐ODD structures and biochemical studies, the results inform on the different PHD.HIFα‐ODD binding modes and the potential effects of clinically observed mutations in HIFα and PHD2 genes. They may help enable new therapeutic avenues, including PHD isoform‐selective inhibitors and sequestration of HIF2α by the PHDs for ccRCC treatment.