The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) gene has been reported to predict a lower risk for developing type 2 diabetes mellitus. However, its effect on the lipid profile has been disputable. Among low-density lipoproteins, small dense low-density lipoprotein (sdLDL) particles have been linked to a greater risk for coronary artery disease. The purpose of this study was to investigate the genetic effect of the Pro12Ala polymorphism in the PPARgamma2 gene on the presence of sdLDL in the general Japanese population. In 379 subjects (aged 54 +/- 13 years), body mass index, percentage of body fat, blood pressure, and biochemical profiles were measured. Pro12Ala polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism. The area of sdLDL subfractions (sdLDL4-7) was analyzed by high-resolution polyacrylamide gel electrophoresis. The frequency of the Ala12 allele in PPARgamma2 was 0.04. There was no difference in total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels between genotypes. However, subjects with the X/Ala genotype (Pro/Ala + Ala/Ala) had significantly higher serum triglyceride levels (P = .001) and a larger area of sdLDL4-7 (P = .002) than those with the Pro/Pro genotype. Multiple regression analysis revealed that the Ala12 allele was a significant variable contributing to the variance in the increased area of sdLDL4-7 (P = .040). In conclusion, the Pro12Ala polymorphism in the PPARgamma2 gene was positively associated with an enlarged area of sdLDL4-7. This polymorphism may play a role in the genetic predisposition to increases in sdLDL4-7.