Background: Preliminary evidence suggests beneficial effects of pure ethyl-eicosapentaenoate (ethyl-EPA) in Huntington disease (HD). Methods: A total of 135 patients with HD were randomized to enter a multicenter. double-blind, placebo-con-trolled trial on the efficacy of 2 g/d ethyl-EPA vs placebo. The Unified Huntington’s Disease Rating Scale (UHDRS) was used for assessment. The primary end point was outcome at 12 months on the Total Motor Score 4 subscale (TMS4). Analysis of covariance (ANCOVA) and a χ2 test on response, defined as absence of increase in the TMS-4, were performed. Results: A total of 121 patients completed 12 months, and 83 did so without protocol violations (PP cohort). Intent-to-treat (ITT) analysis revealed no significant difference between ethyl-EPA and placebo for TMS-4. In the PP cohort, ethyl-EPA proved better than placebo on the χ2 test on TMS-4 (p < 0.05), but missed significance on ANCOVA (p=0.06). Secondary end points (ITT cohort) show-ed no benefit of ethyl-EPA but a significantly worse outcome in the behavioral severity and frequency compared with placebo. Exploring moderators of the efficacy of ethyl-EPA on TMS-4 showed a significant interaction between treatment and a factor defining patients with high vs low CAG repeats. Reported adverse events were distributed equally between treatment arms. Conclusions: Ethyl-eicosapentae-noate (ethyl-EPA) (purity >95%) had no benefit in the intent-to-treat cohort of patients with Huntington disease, but exploratory analysis revealed that a significantly higher number of patients in the per protocol cohort, treated with ethyl-EPA, showed stable or improved motor function. Further studies of the potential efficacy of ethyl-EPA are warranted. Background: Preliminary evidence suggests beneficial effects of pure ethyl-eicosapentaenoate (ethyl-EPA) in Huntington disease (HD). Methods: A total of 135 patients with HD were randomized to enter a multicenter. Double-blind, placebo-con-trolled trial The efficacy of 2 g / d ethyl-EPA vs placebo. The Unified Huntington’s Disease Rating Scale (UHDRS) was used for assessment. The primary end point was outcome at 12 months on the Total Motor Score 4 subscale (TMS4). Analysis of Results: A total of 121 patients completed 12 months, and 83 did so without protocol violations (PP cohort). Intent- In the PP cohort, ethyl-EPA proved better than placebo on the χ2 test on TMS-4 (p <0.05) but but missed significance on ANCOVA (p = 0.06). Secondary end points (ITT cohort) show-ed no benefit of ethyl-EPA but a significant worse outcome in the behavioral severity and frequency compared with placebo. Exploring moderators of the efficacy of ethyl-EPA on TMS-4 showed a significant interaction between treatment and a factor defining patients with high vs low CAG repeats. Reported adverse events were distributed equally between treatment arms. Conclusions: Ethyl-eicosapentae-noate (ethyl-EPA) (purity> 95%) had no benefit in the intent-to-treat cohort of patients with Huntington disease, but exploratory analysis revealed that a significantly higher number of patients in the per protocol cohort, treated with ethyl-EPA, showed stable or improved motor function. Further studies of the potential efficacy of ethyl-EPA are warranted.