This study evaluated the prognostic significance of several risk factors on the outcome of coronary heart disease (CHD) in 639 cardiovascular disease-free subjects with heterozygous familial hypercholesterolaemia (FH). During the 15-year follow-up, 53 (18%) men and 34 (9.8%) women had a CHD event (men vs women, p < 0.001). The age-adjusted 15-year event rate was 3% (87 events/2915 person-years). Smoking increased the CHD risk (hazard ratio = 2.45, p < 0.001), women had a 74% lower risk of a vascular event, compared to men, after controlling for the postmenopausal status (hazard ratio = 0.26, p < 0.001). A one-unit difference in low density lipoprotein (LDL)/high density lipoprotein cholesterol (HDL) cholesterol ratio was associated with a 17% higher risk (hazard ratio = 1.17, p < 0.05); hypertension increased the risk for an adverse event (hazard ratio = 3.02, p < 0.05) and a 1 mg/dl increase in plasma fibrinogen level was associated with a 4% higher CHD risk (hazard ratio = 1.04, p < 0.05). With the power of the 15 years of prospective evaluation, the study shows that increased smoking, hypertension and LDL cholesterol levels eight times more than HDL cholesterol predicts an adverse CHD event, in patients with FH.