Familial combined hyperlipidemia (FCHL) is associated with variable expression of dyslipidemias and insulin resistance. In nondiabetic Pima Indians an A to G substitution in codon 54 of the fatty acid binding protein 2 (FABP2) gene has been shown to be associated with insulin resistance. We screened the entire coding region of this gene by single-strand conformation polymorphism analysis in 24 probands (17 men and 7 women; age, 63.0 +/- 7.4 years [mean +/- SD]; body mass index [BMI], 27.7 +/- 4.2 kg/m2) who had FCHL and in 40 healthy men from a random population sample of 82 men (age, 54.0 +/- 5.0 years; BMI, 26.3 +/- 3.2 kg/m2). Insulin resistance was assessed with the euglycemic clamp in 58 subjects from FCHL families (14 probands with FCHL and 44 first-degree relatives of probands; 38 men and 20 women; age, 51.5 +/- 12.6 years; BMI, 25.5 +/- 3.9 kg/m2). We found three nucleotide substitution in the FABP2 gene: GCT to ACT (Ala-->Thr) in codon 54, GTA to GTG in codon 118, and GCGCA to GCACA in the 3'-noncoding region. Frequencies of these variants did not differ between the patients and control subjects. The Ala to Thr substitution in codon 54 was associated with a high lipid oxidation rate (P = .011 after adjustment for sex and family relationship), high HDL triglycerides (P = .042), and high LDL triglycerides (P = .013) but not with insulin resistance in subjects from FCHL families. The FABP2 gene is unlikely to be a major gene for FCHL, but it might affect lipid metabolism in subjects with FCHL.