Elevated low-density lipoprotein-cholesterol (LDL-C) is regarded as one of major risks of cardiovascular diseases and atherosclerotic events. It has been previously reported that peroxisome proliferator-activated receptors (PPARs) play an important role in the regulation of lipid metabolism. In this study, we aimed to investigate the influence of PPARα/δ/γ gene polymorphisms on LDL-C level. Eight hundred twenty unrelated participants were recruited. Ten single-nucleotide polymorphisms (SNPs) were genotyped to analyze the gene–gene interactions among these polymorphisms using the generalized multifactor dimensionality reduction (GMDR) method. The results of single-locus analyses indicated that the genotypes with minor allele variants at the rs1800206, rs9794, rs1805192, rs709158, and rs3856806 loci are associated with higher LDL-C levels (p<0.05) after adjusting for covariates. In contrast, individuals that were homozygous for the major allele (CC) of rs10865710 had significantly higher LDL-C than those with either one or more minor type alleles (CG+GG, mean difference: −0.21 mM; 95% confidence interval [CI]: −0.37 to −0.04 mM; p=0.013). Significant gene–gene interactions among PPAR gene polymorphisms on LDL-C were identified by a generalized multifactor dimensionality reduction (GMDR) approach in 2- to 8-locus models (p<0.05). Our results provide evidence that multiple PPARα/δ/γ gene polymorphisms are individually associated with increased LDL-C, and that interactions, among these alleles result in additional increased risk suggesting that PPAR genes may contribute substantially to the risk of cardiovascular diseases and atherosclerosis.