Background: Studies suggesting a protective effect of estrogen in neurodegenerative diseases prompted us to investigate this relationship in progressive supranuclear palsy (PSP). Methods: This case-control study evaluated the self-reported reproductive characteristics and estrogen of 150 women with PSP and 150 age-matched female controls who participated in the Environmental Genetic-PSP study. Conditional logistic regression models were generated to examine associations of PSP with estrogen. Results: There was no association between years of estrogen exposure duration and PSP. There was a suggestion of an inverse association between composite estrogen score and PSP that did not reach statistical significance (P =.06). Any exposure to estrogen replacement therapy halved the risk of PSP (odds ratio = 0.52; 95% confidence interval = 0.30-0.92; P =.03). Among PSP cases, earlier age at menarche was associated with better performance on Hoehn and Yahr stage (β = −0.60; SE = 0.26; P =.02) and Unified Parkinson's Disease Rating Scale II score (β = −5.19; SE = 2.48; P =.04) at clinical examination. Conclusions: This case-control study suggests a protective role of lifetime estrogen exposure in PSP. Future studies will be needed to confirm this association. © 2018 International Parkinson and Movement Disorder Society.