Background and Purpose: the benefit/risk analysis of hormone therapy in postmenopausal women is not straightforward and depends on cardiovascular disease. Evidence supports the safety of transdermal estrogens and the importance of progestogens for thrombotic risk. However, the differential association of oral and transdermal estrogens with stroke remains poorly investigated. Furthermore, there are no data regarding the impact of progestogens. Methods: we set up a nested case control study of ischemic stroke (IS) within all French women aged 51 to 62 years between 2009 and 2011 without personal history of cardiovascular disease or contraindication to hormone therapy. Participants were identified using the French National Health Insurance database, which includes complete drug claims for the past 3 years and French National hospital data. We identified 3144 hospitalized IS cases who were matched for age and zip code to 12 158 controls. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). Results: compared with nonusers, the adjusted ORs of IS were1.58 (95% CI, 1.01 2.49) in oral estrogen users and 0.83 (0.56 1.24) in transdermal estrogens users (P<0.01). There was no association of IS with use of progesterone (OR, 0.78; 95% CI, 0.49 1.26), pregnanes (OR, 1.00; 95% CI, 0.60 1.67), and nortestosterones (OR, 1.26; 95% CI, 0.62 2.58), whereas norpregnanes increased IS risk (OR, 2.25; 95% CI, 1.05 4.81). Conclusions: both route of estrogen administration and progestogens were important determinants of IS. Our findings suggest that transdermal estrogens might be the safest option for short-term hormone therapy use.