It is unknown whether the variation in severity of cardiovascular disease (CVD), seen in patients with familial hypercholesterolemia (FH), is reflected in the intima-media thickness (IMT) of carotid and femoral arteries. We measured IMT in both these arteries in 248 consecutive patients with FH, attending our Lipid Clinic. One hundred and six patients were classified as having CVD, while the remaining FH subjects had no clinical evidence of CVD. IMT measurements of 20 prespecified carotid and femoral arterial wall segments of the FH groups with and without CVD were compared. All IMTs in both groups were severely thickened with respect to normal controls. Furthermore, the highest IMTs and the largest absolute differences were observed in the common femoral artery (1.23 +/- 0.46 mm vs 1.10 +/- 0.51 mm; P = 0.006). In subjects with CVD, the distributions of IMT within tertiles for both arterial segments were opposite to those found in FH patients without CVD, (P < 0.05, for both segments). The mean IMT of, in particular, the common femoral artery is thicker in FH individuals with CVD compared with those without. Some FH patients have abnormal IMT of the femoral artery, whereas in others the carotid artery is more affected. Therefore, in FH patients, combined assessment of the carotid and femoral arterial walls provides a more accurate estimation of total atherosclerotic burden in FH.