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The association of each metabolite with clinical parameters and medication was investigated. Mutations in caffeine\u2010associated genes were investigated by direct sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 9 metabolites detected in more than 50% of participants in both cohorts were decreased in 3 parkinsonian disorders compared with healthy controls without any significant association with age at sampling, sex, or disease severity (Hoehn and Yahr stage and Unified Parkinson's Disease Rating Scale motor section) in PD, and levodopa dose or levodopa equivalent dose in PSP and MSA. Of the 9 detected metabolites, 8 in PD, 5 in PSP, and 3 in MSA were significantly decreased in both cohorts even after normalizing to daily caffeine consumption. No significant genetic variations in <jats:italic>CYP1A2<\/jats:italic> or <jats:italic>CYP2E1<\/jats:italic> were detected when compared with controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Serum caffeine metabolic profiles in 3 parkinsonian diseases show a high level of overlap, indicative of a common potential mechanism such as caffeine malabsorption from the small intestine, hypermetabolism, increased clearance of caffeine, and\/or reduced caffeine consumption. \u00a9 2020 The Authors. <jats:italic>Movement Disorders<\/jats:italic> published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder 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