Hormone replacement therapy (HRT) was increasingly promoted over the last 40 years to improve quality of life, and to reduce the risks of osteoporotic fractures and coronary heart disease (CHD). In recent years, observational studies, randomized trials and systematic reviews of such trials have shown that HRT does not reduce, but actually increases cardiovascular risk. HRT increases the relative risks of venous thromboembolism (twofold), and of fatal or disabling stroke (by 50%); whilst increasing the early risk of myocardial infarction and having no protective effect against CHD on longer term use. Possible mechanisms for these increased cardiovascular risks include down-regulation of several inhibitory pathways of blood coagulation, resulting in increased coagulation activation, which promotes venous and arterial thrombosis. The implications for prescription are discussed, as are lessons for future evaluation of health care interventions.