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Several genetic and environmental factors have been reported in progressive supranuclear palsy (PSP), although none were identified as a definitive cause. We aimed to explore potential gene-environment interactions in PSP. Two hundred and ninety two PSP cases and 292 controls matched for age, sex, and race from the ENGENE-PSP were analyzed to determine the association between PSP and minor alleles of 5 single nucleotide polymorphisms (SNPs) in 4 genes (MAPT, MOBP, EIF2AK3, and STX6), which were previously associated with PSP risk. Interactions between these SNPs and environmental factors, including previously reported occupational and agricultural risk factors for PSP, were assessed for PSP odds and age of symptom onset. Minor alleles of MAPTrs242557 and EIF2AK3rs7571971 were individually associated with increased odds; MAPTrs8070723 minor alleles were associated with lower PSP odds. There were several gene-environment interactions for PSP odds and age of symptom onset, however, they did not remain significant after FDR-correction. Larger scale studies are required to determine potential interactions., Competing Interests: IL supported by the National Institutes of Health grants: 2R01AG038791-06A, U01NS090259, U01NS100610, U01NS80818, R25NS098999, P20GM109025; U19 AG063911-1; 1R21NS114764-01A1; Michael J Fox Foundation, Lewy Body Association, Abbvie, Biogen, Centogene, Roche, EIP-Pharma and Biohaven Pharmaceuticals. She was member of a Lundbeck Advisory Board. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. DSt supported by the Abbvie, Inc., the American Parkinson Disease Association, the Michael J. Fox Foundation for Parkinson Research, Alabama Department of Commerce, the Department of Defense, and NIH grants P50NS108675, R25NS079188, and T32NS095775. He has a clinical practice and is compensated for these activities through the University of Alabama Health Services Foundation. He has served as a consultant for or received honoraria from Abbvie Inc., Sutter Health, the International Parkinson Disease and Movement Disorder Society, Theravance, McGraw Hill, and Sanofi-Aventis. He is a member of the faculty of the University of Alabama at Birmingham and is supported by endowment and University funds. CM received research funding from The Michael J Fox Foundation, Canadian Institutes of Health Research, Parkinson's Foundation (US), International Parkinson and Movement Disorders Society. She is employed by University Health Network, contracted by Grey Matter Technologies, and receives financial compensation as a steering committee member from the Michael J Fox Foundation. DSh employed by Banner Health, received research support from the Arizona Alzheimer's Consortium, Abbvie, Acadia, Aptinyx, Axovant, Biogen, Eisai, Eli Lilly, Enterin, Neurocrine, Michael J Fox Foundation, NIH, Nuvelution, Theravance and Teva; consultant fees from Amneal, Forensis and Neurocrine; speaker honoraria from Acorda, Neurocrine, Sunovion, Teva and US World Meds. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Litvan, Proudfoot, Martin, Standaert, Riley, Hall, Marras, Bayram, Dubinsky, Bordelon, Reich, Shprecher, Kluger, Cunningham, Schellenberg and Jankovic.)