Background and Purpose— Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α, PPARGC1A ) integrates the transcriptional program of mitochondrial biogenesis. Mitochondria are the main source of cellular reactive oxygen species implicated in atherogenesis. We therefore ascertained associations of PPARGC1A polymorphisms with asymptomatic carotid atherosclerosis. Methods— Eight single nucleotide polymorphisms tagging two haplotype blocks within PPARGC1A were studied in 1379 participants of the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk. Early atherosclerosis was assessed by intima-media thickness and extent of plaques (B-score) of the carotid arteries. Results— No associations of carotid artery intima-media thickness measurements with block 1 or 2 haplotype distributions or individual haplotypes were observed. However, the block 1 haplotype carrying the variant C nucleotide at −3974 relative to the transcription start site was associated with disease status defined by the presence of more than one minimal lesion and the −3974 C allele was associated with decreased risk (odds ratio=0.60, P =0.007) after adjustment for linkage disequilibrium between single nucleotide polymorphisms. Conclusions— These result are consistent with the concept that risk factors for distinct carotid phenotypes may vary and suggest, but do not prove, that PGC-1α may contribute to the regulation of atherogenic pathways.