BACKGROUND: We examined whether the discrepancy between observational studies and randomized clinical trials (RCTs) on the effect of hormone replacement therapy (HRT) on myocardial infarction (MI) could be explained by differences in age of participants at the time of either HRT initiation or the MI event. METHODS: A matched case-control study was performed using the General Practice Research Database. Cases (n = 22 225) had a first diagnosis of MI between 1987 and 2001; up to six controls (n = 144 085) were matched to each case based on age, sex, and practice. Conditional logistic regression was performed adjusting for traditional cardiovascular risk factors, as well as, cardiovascular drug use and consultation rate. RESULTS: HRT users had a lower overall risk of MI compared with never users [odds ratio (OR): 0.76; 95% confidence interval (95% CI) 0.68-0.86); results were similar for opposed (OR: 0.73; 95% CI 0.68-0.86) and unopposed (OR: 0.79; 95% CI 0.66-0.96) therapy. This apparent benefit increased with older age at HRT initiation(18-44 years: OR = 0.99; 95% CI 0.74-1.33; 45-54 years: OR = 0.84; 95% CI 0.71-1.00; 55-64 years: OR = 0.67; 95% CI 0.54-0.82; 65-74 years: OR = 0.50; 95% CI 0.34-0.74; >75 years: OR = 0.55; 95% CI 0.23-1.32). Moreover, the cardioprotective effect was greater for MIs occurring at older ages (P-value for interaction = 0.003). CONCLUSION: The effect of HRT on MI becomes more pronounced with older age at initiation and at older ages at the time of an MI event. These findings contradict the hypothesis that the apparent protection seen in observational studies was due to the inclusion of younger participants.