BACKGROUND Suppression of prostacyclin (PGI2) is implicated in the cardiovascular hazard from inhibitors of cyclooxygenase (COX)-2. Furthermore, estrogen confers atheroprotection via COX-2-dependent PGI2 in mice, raising the possibility that COX inhibitors may undermine the cardioprotection, suggested by observational studies, of endogenous or exogenous estrogens. RESULTS To identify an interaction between hormone therapy (HT) and COX inhibition, we measured a priori the association between concomitant nonsteroidal anti-inflammatory drugs (NSAIDs), excluding aspirin, in peri- and postmenopausal women on HT and the incidence of myocardial infarction (MI) in a population-based epidemiological study. The odds ratio (OR) of MI in 1,673 individuals and 7,005 controls was increased from 0.66 (95% confidence interval [CI] 0.50-0.88) when taking HT in the absence of traditional (t)NSAIDs to 1.50 (95% CI 0.85-2.64) when taking the combination of HT and tNSAIDs, resulting in a significant (p < 0.002) interaction. The OR when taking aspirin at doses of 150 mg/d or more was 1.41 (95% CI 0.47-4.22). However, a similar interaction was not observed with other commonly used drugs, including lower doses of aspirin, which target preferentially COX-1. CONCLUSIONS Whether estrogens confer cardioprotection remains controversial. Such a benefit was observed only in perimenopausal women in the only large randomized trial designed to address this issue. Should such a benefit exist, these results raise the possibility that COX inhibitors may undermine the cardioprotective effects of HT.