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Background: Results from previous studies regarding relationships between age at menarche and cardiovascular disease remain controversial. This study investigated the association between endogenous estrogen exposure and ischemic stroke risk. Methods: A total of 189 ischemic stroke patients and 192 age-matched healthy postmenopausal women were recruited. Age at menarche and menopause and risk factors of ischemic stroke were recorded through structured questionnaires by well-trained research assistants. Lifetime estrogen exposure was calculated as the number of years between age of menarche and menopause. Results: Study subjects with a history of hypertension and diabetes mellitus have a 2.8- and 6.2-fold increased risk for ischemic stroke, respectively. In addition, study subjects with waist circumferences ≥ 80cm also have a 2.6-fold increased risk of ischemic stroke. Conversely, subjects who experienced menarche at an early age may have a significantly decreased risk of 0.3-fold for ischemic stroke. Moreover, there was a significant and joint protective effect for study subjects without any risk factors of ischemic stroke, including a history of hypertension and diabetes mellitus, late age at menarche, and shorter lifetime estrogen exposure; these subjects were found to have the lowest risk (0.03-fold) for the development of ischemic stroke. Conclusion: Our study provides strong evidence that a significant joint protective effect was observed for patients who undergo early menarche, have longer estrogen exposure and no history of hypertension or diabetes mellitus on the risk of ischemic stroke.