Insulin resistance has been associated with hypertriglyceridemia, combined hyperlipidemia, and familial combined hyperlipidemia (FCHL). Whether all FCHL patients with different types of dyslipidemia have low insulin sensitivity has not been evaluated. We measured insulin sensitivity by the hyperinsulinemic euglycemic clamp with indirect calorimetry in 110 healthy controls and in 105 nondiabetic, FCHL family members: in 50 without dyslipidemia, in 19 with hypercholesterolemia (total cholesterol >/=7.7 mmol/L), in 22 with hypertriglyceridemia (total triglycerides >/=2.4 mmol/L in men 2.4 mmol/L in women), and in 14 with combined hyperlipidemia. During the hyperinsulinemic clamp, FCHL family members had higher free fatty acid levels than did controls (0.06+/-0.06 [mean+/-SD] in controls versus 0.16+/-0.11 in relatives without dyslipidemia versus 0.15+/-0. 07 in hypercholesterolemic patients versus 0.29+/-0.14 in hypertriglyceridemic patients versus 0.27+/-0.17 mmol/L in patients with combined hyperlipidemia; P<0.001 after adjustment for age, sex, and body mass index). Relatives without dyslipidemia (16.4+/-4.4 micromol. kg(-1). min(-1), P=0.001) and patients with hypertriglyceridemia (12.8+/-3.8 micromol. kg(-1). min(-1), P<0.001) and with combined hyperlipidemia (13.7+/-3.1 micromol. kg(-1). min(-1), P<0.001) had lower rates of insulin-stimulated glucose oxidation than did controls (19.4+/-4.7 micromol. kg(-1). min(-1)). Also, the rates of nonoxidative glucose disposal were lower in patients with hypertriglyceridemia (P=0.001) and combined hyperlipidemia (P=0.011) than in controls. In contrast, subjects with hypercholesterolemia and control subjects had similar rates of insulin-stimulated glucose uptake. We conclude that a defect in free fatty acid suppression during hyperinsulinemia, probably located in adipose tissue, is characteristic for all FCHL patients with varying types of dyslipidemia, whereas insulin resistance in skeletal muscle is observed only in FCHL patients with elevated triglyceride levels.