Familial combined hyperlipidemia (FCH) is a heterogeneous lipid disorder, caused by overproduction of VLDL and characterized by the occurrence of small, dense LDL particles, all features that are also associated with insulin resistance. Therefore, insulin sensitivity was examined directly by means of the euglycemic hyperinsulinemic clamp technique in male nonobese, normotensive FCH patients and compared with that of their nonaffected relatives, matched for age and body mass index (BMI). In addition, an oral 75-g glucose tolerance test (OGTT) was performed and lipid values, including the LDL subfraction profile, were determined. During the clamp, forearm blood flow (FBF) was measured by venous occlusion plethysmography. All participants had a normal glucose response after the glucose load, whereas FCH patients showed hyperinsulinemia after OGTT and higher fasting C-peptide levels. During the clamp, insulin concentrations increased equally in both groups. Mean whole-body glucose uptake (M) (120 to 180 minutes) was lower in FCH patients than in nonaffected relatives (6.89 +/- 0.31 versus 8.94 +/- 0.76 mg.kg-1.min-1; P = .01). In addition, the glucose uptake per unit insulin (I) was lower in FCH patients (insulin sensitivity index [M/I], 7.46 +/- 0.50 versus 9.51 +/- 0.53; P = .009). M significantly correlated with BMI, plasma cholesterol and triglyceride concentrations, and the individual LDL density. The FBF correlated with insulin sensitivity and increased significantly in nonaffected relatives (1.9 +/- 0.12 to 2.5 +/- 0.4 mL.min-1.dL-1; P = .025) but not in patients. Thus, FCH patients characterized by a predominance of small, dense LDL are insulin resistant compared with their nonaffected relatives. This insulin resistance may partly be explained by a decreased insulin-induced vasodilation in skeletal muscle.