BACKGROUND: Antidopaminergic medications (ADM) are often used for symptom management of Huntington's disease (HD). Evidence from past research suggests that ADMs are associated with worse clinical outcomes in HD, but their impact on various domains remains underexplored. OBJECTIVE: We used causal inference analysis to understand the impact of ADM use on measures of clinical progression in HD across multiple domains over 2 years. METHODS: We used the Enroll-HD database with a new-user design, which compared a cohort that initiated ADM use after the first visit with an unexposed cohort that remained off ADMs. To control for 27 covariates, we used a doubly robust targeted maximum likelihood estimation and conducted two analyses. First, we analyzed ADM treatment 2 years post-baseline and separately for 12 outcome measures. Second, we examined the association of ADM dose with measures of clinical outcomes. RESULTS: The ADM-exposed group exhibited faster change in measures of clinical outcome compared with the off-ADM group, which was statistically reliable in cognitive and functional outcome measures, and the composite Unified Huntington's Disease Rating Scale (cUHDRS). Motor domain analyses showed faster change in bradykinesia in the ADM-exposed group versus off-ADM but no difference in chorea or total motor score (TMS). Higher ADM doses also showed greater differences compared to the off-ADM group. CONCLUSIONS: ADM use was associated with more rapid change in clinical measures, particularly in cognitive and functional domains. However, assumptions required to establish causation between ADM use and disease progression may not have been fully met, and further research is warranted. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.