Rationale: Targeting vascular smooth muscle cell (VSMC) phenotypic switching is a promising therapeutic approach for atherosclerosis. Dysregulation of PGC1 alpha (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha), a key regulator of cellular energy metabolism, has been implicated in the pathogenesis of atherosclerosis, yet its role in atherosclerosis remains controversial. Objective: The current study aimed to determine whether and how PGC1 alpha in VSMCs regulates atherosclerosis progression. Methods and Results: We generated transgenic rabbits with SMC-specific PGC1 alpha overexpression and showed that these rabbits developed significantly less aortic atherosclerosis than their nontransgenic littermates after high-cholesterol diet feeding, while total plasma cholesterol levels were similar. As indicated by the restored expression of VSMC differentiation marker genes, the high-cholesterol diet-induced phenotypic switching in the aortic media was largely reversed in transgenic rabbits, accompanied by decreased levels of synthetic phenotype genes, proinflammatory cytokines, adhesion molecules, macrophage infiltration, MMPs (matrix metalloproteinases), reactive oxygen species production and senescence. Ex vivo studies further showed that VSMC-specific PGC1 alpha overexpression markedly suppressed the promotive effect of high-cholesterol diet feeding on the association of SRF (serum response factor) with ELK1 (ETS transcription factor ELK1), a TCF (ternary complex factor) that acts as a myogenic repressor in VSMCs, thereby preserving the VSMC contractile phenotype. Furthermore, knockdown of PGC1 alpha remarkably increased ERK (extracellular signal-regulated kinase)1/2-ELK-1 signaling, which promoted phenotypic switching and proliferation of cultured rabbit VSMCs. In addition, we showed that PGC1 alpha can regulate EGFR (epidermal growth factor receptor)-ERK1/2 MAPK (mitogen-activated protein kinase) signaling via modulating PPAR gamma (peroxisome proliferator-activated receptor gamma) activity in RVSMCs (rabbit vascular smooth muscle cells). Finally, we showed that these beneficial results of SMC-specific PGC1 alpha overexpression can be extrapolated from rabbits to human VSMCs and clinical settings. Conclusions: We demonstrated a critical role of PGC1 alpha in maintaining the contractile phenotype of VSMCs and highlighted the therapeutic potential of PGC1 alpha for atherosclerosis.