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Abstract Background Huntington’s disease (HD) causes progressive loss of function, cognition, and motor control, with no approved therapy yet shown to slow disease progression. In the PROOF-HD phase 3 trial, pridopidine did not meet the primary or key secondary outcomes in the overall population, but participants who remained off antidopaminergic medications (ADMs) showed benefits compared to placebo during the double-blind phase. Whether such benefits continue with longer duration treatment and how they compare with expected natural-history trajectories remains unknown. Methods We evaluated outcomes through Week 104 from baseline in participants who received continuous pridopidine (45 mg twice daily) and remained off-ADMs throughout the double-blind and open-label extension period (n=90). External comparators from ENROLL-HD and TRACK-HD were constructed using propensity-score weighting methods. Least-squares mean changes from baseline to Week 104 were estimated using mixed-effects models for repeated measures across outcomes. Results At two-years, pridopidine treatment was associated with benefits versus propensity-score weighted natural-history comparators across multiple outcomes. Relative to ENROLL-HD, participants receiving pridopidine showed slowing of progression over 104 weeks, expressed as percent slowing across cUHDRS, TFC, SWR, SDMT, and TMS outcomes (39.5–88.3% slowing). Similar patterns were observed relative to TRACK-HD across the same measures (48.5 – 81.5% slowing), including quantitative motor performance assessed by Q-Motor FT-IOI (77.8% slowing). Exploratory analyses including participants receiving concomitant ADMs showed similar directional patterns as the primary analyses. Conclusions In a two-year follow-up, continuous pridopidine treatment in participants remaining off-ADMs was associated with slower clinical progression relative to expected natural-history trajectories. (Clinical Trials Identifier: NCT04556656 )