Blood flow through healthy human vessels releases NO to produce vasodilation, whereas in patients with coronary artery disease (CAD), the mediator of dilation transitions to mitochondria-derived hydrogen peroxide ( _mt H ₂ O ₂ ). Excessive _mt H ₂ O ₂ production contributes to a proatherosclerotic vascular milieu. Loss of PGC-1α (peroxisome proliferator–activated receptor γ coactivator 1α) is implicated in the pathogenesis of CAD. We hypothesized that PGC-1α suppresses _mt H ₂ O ₂ production to reestablish NO-mediated dilation in isolated vessels from patients with CAD. Isolated human adipose arterioles were cannulated, and changes in lumen diameter in response to graded increases in flow were recorded in the presence of PEG (polyethylene glycol)–catalase (H ₂ O ₂ scavenger) or L-NAME ( N ^G -nitro- l -arginine methyl ester; NOS inhibitor). In contrast to the exclusively NO- or H ₂ O ₂ -mediated dilation seen in either non-CAD or CAD conditions, respectively, flow-mediated dilation in CAD vessels was sensitive to both L-NAME and PEG-catalase after PGC-1α upregulation using ZLN005 and α-lipoic acid. PGC-1α overexpression in CAD vessels protected against the vascular dysfunction induced by an acute increase in intraluminal pressure. In contrast, downregulation of PGC-1α in non-CAD vessels produces a CAD-like phenotype characterized by _mt H ₂ O ₂ -mediated dilation (no contribution of NO). Loss of PGC-1α may contribute to the shift toward the _mt H ₂ O ₂ -mediated dilation observed in vessels from subjects with CAD. Strategies to boost PGC-1α levels may provide a therapeutic option in patients with CAD by shifting away from _mt H ₂ O ₂ -mediated dilation, increasing NO bioavailability, and reducing levels of _mt H ₂ O ₂ . Furthermore, increased expression of PGC-1α allows for simultaneous contributions of both NO and H ₂ O ₂ to flow-mediated dilation.