Familial combined hyperlipidemia (FCHL) is a common genetic lipid disorder characterized by premature coronary artery disease, dyslipidemia, insulin resistance, and impaired adipose tissue free fatty acid (FFA) metabolism. Increased adipose tissue FFA flux towards the liver may, in part, contribute to reduced insulin sensitivity and hyperlipidemia in FCHL. It was the objective of the present study to evaluate the contribution of the peroxisome proliferator-activated receptor gamma (PPARgamma) gene to FCHL traits related to adipocyte lipid metabolism, dyslipidemia, and insulin resistance. In a case-control panel consisting of 79 FCHL probands and 124 spouse controls, polymorphic marker D3S1259 and three intragenic PPARgamma variants, i.e., 161C > T, Pro12Ala, and Pro115Gln, were studied. The Pro115Gln variant was not found in any of the subjects. Allele frequencies of the 161C > T, Pro12Ala variants, and D3S1259 did not differ significantly between FCHL probands and spouses. In FCHL probands, individuals heterozygous or homozygous for the 161T allele had lower plasma concentrations of FFA (P < 0.05) and glycerol (P < 0.01). No significant associations were found in spouses. These findings identify PPARgamma as a quantitative trait locus for FFA and glycerol, against a background of insulin resistance for adipose tissue lipid metabolism, and therefore as a modifier gene in FCHL.