The Heart and Estrogen/Progestin Replacement Study (HERS) was the first randomised, double-blind, placebo-controlled study to evaluate the outcome of hormone replacement therapy (HRT) on subsequent cardiac events in postmenopausal women with established coronary heart disease (CHD). Of the 2763 women enrolled, 1380 were randomised to receive 0.625mg of conjugated equine estrogens plus 2.5mg of medroxyprogesterone daily (Prempro) and 1383 were randomised to receive a placebo. The results were surprising: 179 women in the hormone group and 182 women in the placebo group experienced either a nonfatal myocardial infarction or CHD death (relative hazard 0.99, 95% confidence interval 0.81 to 1.22). This occurred despite a net 11% reduction in low density lipoprotein (LDL) and a net 10% increase in high density lipoprotein (HDL) after 1 year of follow-up (p < 0.001 for LDL and HDL). Also, there were no differences between the 2 treatment groups in any secondary cardiovascular outcomes. The overall null effect may have been the result of an unexpected early adverse effect of the HRT regimen that offset a later reduction in risk. Clearly, the use of HRT for secondary prevention of heart disease is more complex than was initially believed. More data are needed from other clinical trials concerning the risks and benefits of HRT to confirm or refute the puzzling HERS results. HERS also underscores the need for trials with clinical end-points to evaluate both the safety and efficacy of drug therapy. Although observational studies are useful, they cannot provide definitive answers regarding treatment recommendations. Until further data are available, clinicians should not use estrogen plus medroxyprogesterone for the sole purpose of secondary prevention of CHD.