Summary. We investigated the effect of prothrombotic coagulation defects in combination with smoking and other conventional risk factors on the risk of myocardial infarction in young women. In 217 women with a first myocardial infarction before the age of 50 years and 763 healthy control women from a population-based case–control study, factor V Leiden and prothrombin 20210A status were determined. Data on major cardiovascular risk factors and oral contraceptive use were combined with the presence or absence of these prothrombotic mutations, and compared between patients and controls. The overall odds ratio for myocardial infarction in the presence of a coagulation defect was 1·1 [95% confidence interval (CI) 0·6–1·9]. The combination of a prothrombotic mutation and current smoking increased the risk of myocardial infarction 12-fold (95% CI 5·7–27) compared with non-smokers without a coagulation defect. Among women who smoked cigarettes, factor V Leiden presence versus absence increased the risk of myocardial infarction by 2·0 (95% CI 0·9–4·6), and prothrombin 20210A presence versus absence had an odds ratio of 1·0 (95% CI 0·3–3·5). We conclude that factor V Leiden and prothrombin 20210A do not add substantially to the overall risk of myocardial infarction in young women. However, in women who smoke, the presence of factor V Leiden increased the risk of myocardial infarction twofold.