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<h3>Abstract</h3> <h3>Importance</h3> Biomarkers for the early detection of Parkinson’s disease (PD) are needed. Patients with PD display differences in peripheral blood biomarkers of immune function, including leukocyte differential counts and C-reactive protein (CRP), compared to controls. These differences may be useful biomarkers to predict PD, and may shed light on PD pathogenesis. <h3>Objectives</h3> To identify whether peripheral immune dysregulation is a pre-diagnostic feature of PD, and whether it plays a causal role. <h3>Design</h3> Cross-sectional association analysis of the relationship between differential leukocyte count and other markers of acute inflammation at enrolment, and incident cases of PD in UK Biobank. We used Mendelian randomization to establish whether differences in leukocyte differential counts have a causal influence on risk of PD. <h3>Setting</h3> UK Biobank; a population-based cohort with over 500,000 participants aged 40-69 recruited in the UK between 2006 and 2010. <h3>Participants</h3> PD cases were defined as individuals with an ICD-10 coded diagnosis of PD. Cases were defined as ’incident’ if their age at diagnosis was greater than their age at recruitment to UKB. ’Controls’ were defined as individuals without a diagnosis of PD. After applying exclusion criteria for pre-existing health conditions that can influence blood counts, 507 incident PD cases and 328,280 controls were included in the analysis. <h3>Exposure</h3> Blood cell markers (absolute and relative counts) and other markers of inflammation were obtained from blood tests of participants taken at the initial visit. <h3>Results</h3> Lower lymphocyte count was associated with increased odds of incident PD (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.65-0.90). There was weaker evidence of association between lower eosinophil and monocyte counts, lower CRP, and higher neutrophil counts on risk of incident PD. The association between lymphopenia and incident PD remained robust to sensitivity analyses. Mendelian randomization analyses suggested that the effect of low lymphocyte count on PD risk was causal (OR 0.91, 95% CI 0.85 - 0.99). <h3>Conclusions and relevance</h3> In this large, prospective setting, lower lymphocyte count was associated with higher risk of subsequent PD diagnosis. Furthermore genetic evidence supported a causal role for lymphocyte count on PD risk. <h3>Key points</h3> <h3>Question</h3> Is the leukcoyte differential count a feature of pre-diagnostic Parkinson’s disease? <h3>Findings</h3> In the UK Biobank, a longitudinal cohort study with over 500,000 participants, lower lymphocyte count was associated with a 23% increased odds of incident PD, a significant difference. Mendelian randomisation revealed a convincing causal effect for low lymphocyte count on PD risk. <h3>Meaning</h3> Pre-diagnostic Parkinson’s disease is associated with lower lymphocyte counts; the suggestion of causal effect may shed light on PD pathogenesis.