Familial combined hyperlipidemia (FCHL) is a common genetic lipid disorder that is present in 10% of patients with premature coronary artery disease (CAD). It was the objective of the present study to evaluate the possible involvement of the PPARA locus in the pathophysiology of FCHL. Mutation detection analyses of the six coding PPARA exons resulted in the identification of four novel variants, [C/T] intron 3, S234G, [G/A] intron 5, and [C/A] 3(') UTR in three FCHL probands, whereas no novel variants were identified in spouses. In a case-control study, markers D22S275 and D22S928 were shown not to be associated with FCHL. However, D22S928, mapped within 1Mb of the PPARA gene, was shown to have a modifying effect on plasma apoCIII concentrations (P=0.011) and the combined hyperlipidemic FCHL phenotype (P=0.038). In addition two PPARA polymorphisms in intron 2 and 7 were studied, but these were not associated with FCHL. The frequency of the L162V variant was less in FCHL probands (1.98%) compared to that in spouses (4.84%). These results clearly demonstrate the genetically complex nature of FCHL and identify the PPARA gene as a modifier of the FCHL phenotype.