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Blood biomarkers of neuronal damage could facilitate clinical management of and therapeutic development for Huntington’s disease. We investigated whether neurofilament light protein (NfL) in blood is a potential prognostic marker of neurodegeneration in patients with Huntington’s disease.In the 3 year, 298-participant TRACK-HD cohort, we did a retrospective analysis of the relationship between plasma NfL and clinical and neuroimaging measures previously identified as being the strongest predictors of HD progression. Cross-sectional and longitudinal relationships were analysed using random effect models of within-subject correlation. In a separate 37-participant cohort we quantified NfL in cerebrospinal fluid (CSF) and plasma.Mean concentrations of plasma NfL at baseline were significantly higher in HTT mutation carriers than in controls and the difference increased with disease stage. At any given timepoint, plasma NfL correlated with clinical and MRI findings. In longitudinal analyses, baseline plasma NfL correlated significantly with subsequent decline in cognition (SDMT r=–0.374, p<0.0001; SWR r=–0.248, p=0.0033), TFC (r=–0.289, p=0.0264), and brain atrophy (caudate r=0.178, p=0.0087; whole-brain r=0.602, p<0.0001; grey matter r=0.518, p<0.0001; white matter r=0.588, p<0.0001; and ventricular expansion r=–0.589, p<0.0001). All changes except SWR and TFC remained significant after adjustment for age and CAG repeat. In premanifest HD individuals, plasma NfL at baseline was associated with subsequent clinical onset during the 3 year follow-up period. Concentrations of NfL in CSF and plasma were correlated in mutation carriers.Interpretation NfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington’s disease.