Background— Soy and isoflavones have been proposed to reduce the risk of cardiovascular risk factors, but their potential as preventatives for cardiovascular disease remains uncertain. We investigated the association of soy and isoflavone intake with risk of cerebral and myocardial infarctions (CI and MI). Methods and Results— To examine the association of soy and isoflavone intake with the risk of CI and MI, we studied 40 462 Japanese (40 to 59 years old, without cardiovascular disease or cancer at baseline). They completed a food-frequency questionnaire (1990–1992) and received follow-up to 2002. After 503 998 person-years of follow-up, we documented incidence of CI (n=587) and MI (n=308) and of mortality for CI and MI combined (n=232). For women, the multivariable hazard ratios and 95% confidence limits for soy intake ≥5 times per week versus 0 to 2 times per week were 0.64 (0.43 to 0.95) for risk of CI, 0.55 (0.26 to 1.09) for risk of MI, and 0.31 (0.13 to 0.74) for cardiovascular disease mortality. Similar but weaker inverse associations were observed between intake of miso soup and beans and risk of cardiovascular disease mortality. The multivariable hazard ratios for the highest versus the lowest quintiles of isoflavones in women were 0.35 (0.21 to 0.59) for CI, 0.37 (0.14 to 0.98) for MI, and 0.87 (0.29 to 2.52) for cardiovascular disease mortality. An inverse association between isoflavone intake and risk of CI and MI was observed primarily among postmenopausal women. No significant association of dietary intake of soy, miso soup, and beans and isoflavones with CI or MI was present in men. Conclusions— High isoflavone intake was associated with reduced risk of CI and MI in Japanese women. The risk reduction was pronounced for postmenopausal women.