Background Identifying sex‐related differences is critical for enhancing our understanding of factors that may impact prognosis and advance treatments in Huntington's disease (HD). Objectives To investigate if sex‐related differences exist in clinical HD. Methods Longitudinal study of the Enroll‐HD database. Manifest HD patients were included in the analysis (N = 8401). Linear mixed models were used to assess motor, behavioral, and cognitive functioning over a series of four annual visits, and compared male and female HD gene carriers. Results HD patients showed significant sex‐dependent differences in motor, cognitive, and behavioral symptoms. Both sexes had worsened motor symptoms over the course of four visits, but there was a significant disparity between sexes, with females consistently presenting with more symptoms than males. For behavioral symptoms, specifically depressive symptoms, females had significantly more depressive symptoms, although self‐reported symptoms in both sexes became less severe throughout time. Conclusions Our analyses suggest that women have worse symptoms than men during the course of HD.

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