We show here that mice hypomorphic for hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2) (Hif-p4h-2 (gt/gt)), the main regulator of the stability of the HIFα subunits, have normoxic stabilization of HIF-1α and HIF-2α in their skeletal muscles. The size of the capillaries, but not their number, was increased in the skeletal muscles of the Hif-p4h-2 (gt/gt) mice, whereas the amount of glycogen was reduced. The expression levels of genes for glycolytic enzymes, glycogen branching enzyme 1 and monocarboxylate transporter 4, were increased in the Hif-p4h-2 (gt/gt) skeletal muscles, whereas no significant increases were detected in the levels of any vasculature-influencing factor studied. Serum lactate levels of the Hif-p4h-2 (gt/gt) mice recovered faster than those of the wild type following exercise. The Hif-p4h-2 (gt/gt) mice had elevated hepatic phosphoenolpyruvate carboxykinase activity, which may have contributed to the faster clearance of lactate. The Hif-p4h-2 (gt/gt) mice had smaller infarct size following limb ischemia-reperfusion injury. The increased capillary size correlated with the reduced infarct size. Following ischemia-reperfusion, glycogen content and ATP/ADP and CrP/Cr levels of the skeletal muscle of the Hif-p4h-2 (gt/gt) mice were higher than in the wild type. The higher glycogen content correlated with increased expression of phosphofructokinase messenger RNA (mRNA) and the increased ATP/ADP and CrP/Cr levels with reduced apoptosis, suggesting that HIF-P4H-2 deficiency supported energy metabolism during ischemia-reperfusion and protection against injury. Key messages: HIF-P4H-2 deficiency protects skeletal muscle from ischemia-reperfusion injury. The mechanisms involved are mediated via normoxic HIF-1α and HIF-2α stabilization. HIF-P4H-2 deficiency increases capillary size but not number. HIF-P4H-2 deficiency maintains energy metabolism during ischemia-reperfusion.