The study objective was to investigate the relationship of insulin resistance (IR) with the lipoprotein phenotype in familial combined hyperlipidemia (FCH). Thirty-seven FCH men diagnosed by clinical and biochemical criteria and classified as lipoprotein phenotype IIa (n = 9), IIb (n = 17), or IV (n = 11) were compared with a healthy control group of 30 men of similar age, body mass index (BMI), waist to hip ratio (WHR), and systolic and diastolic blood pressure. In all subjects, the plasma lipoprotein profile and baseline and post-oral glucose tolerance test (OGTT) glucose and insulin plasma values were measured. An intravenous glucose tolerance test was performed and IR was studied by the peripheral insulin sensitivity index (Si). After the OGTT, significantly higher values for insulinemia (at 0, 60, 90, and 120 minutes) and the area under the curve (AUC) of insulin secretion were observed in FCH. The AUC of insulin was greater in FCH subjects with the hypertriglyceridemic phenotype as compared with the controls and significantly lower Si levels, indicating greater IR, were found in the three FCH groups (control, 3.48 +/- 1.87 mU/L/min; FCH IIa, 2.09 +/- 1.08; FCH IIb, 1.54 +/- 0.77; FCH IV, 1.47 +/- 0.93; P < .001). The prevalence of IR (Si < 2 x 10(-4) mU/L/min) was greater in FCH, independent of the lipoprotein phenotype, as compared with the controls (P < .0001). Higher plasma glucose and insulin levels at 120 minutes and lower Si values were found in the FCH IIa group compared with the controls (P < .05), indicating a state of IR in this subgroup of normotriglyceridemic subjects. In conclusion, IR was found in the three FCH lipoprotein phenotypes, being more severe in subjects with hypertriglyceridemia. Hence, the therapeutic goals in FCH should include measures to normalize plasma lipids and improve peripheral insulin sensitivity.