Clinical management of heterozygous familial hypercholesterolaemia is largely based on evidence from a small number of observational studies and extrapolation from the results of clinical trials of lipid-lowering in patients with polygenic hypercholesterolaemia The objectives of this study were (i) to determine the absolute and relative mortality of patients with treated heterozygous familial hypercholesterolaemia, (ii) to estimate the effect of changes in treatment efficacy on mortality trends over time, and (iii) to examine the implications of these findings for patient management. A cohort of 605 men and 580 women aged 20-79 years with heterozyous familial hypercholesterolaemia were recruited from 21 out-patient lipid clinics in the UK. Patients were followed prospectively from 1980 to 1995 for 8770 person-years. Absolute mortality was calculated, and relative risk was expressed as the ratio of the number of observed deaths to the number expected in the general population of England and Wales. Forty six of the 73 deaths were due to coronary heart disease. In women aged 20-39, despite treatment, the relative risk of a fatal coronary event was increased 125-fold (95% confidence intervals 15-451) and the annual coronary mortality was 0.17%. In men aged 20-39 the relative risk was increased 48-fold (17-105) and the annual coronary mortality was 0.46%. The relative risk decreased with age but the absolute risk increased. For men and women aged 60-79, the annual coronary mortality was 1.1% representing a significant excess mortality for women (relative risk 2.6, 1.3-4.5) but not for men (RR 1.1, 0.5-2.3). Non-coronary mortality was not increased at any age (RR for all ages 0.68, 0.45-0.99). There was a decline in the relative risk for coronary mortality in patients aged 20-59 from an eight-fold (4.8-7.2) increased risk before 1992 to 3.7 (1.6-7.2.) thereafter (P=0.08). The results suggest that the prognosis for patients with heterozygous familial hypercholesterolaemia has improved with the introduction of more effective treatment, and that lipid-lowering therapy is not associated with increased non-coronary mortality. These findings and the excess coronary mortality observed suggest that all affected adult men and post-menopausal women should be treated with HMG-CoA reductase inhibitors.