BACKGROUND: Upper limb dysfunction is common in people with multiple sclerosis (pwMS), significantly affecting daily activities and quality of life. While dalfampridine has shown efficacy in improving gait in pwMS, its impact on upper extremity function remains unclear. OBJECTIVES: To evaluate the effect of sustained-release oral dalfampridine on upper extremity function in pwMS. DESIGN: A randomized, placebo-controlled trial. METHODS: In all, 30 pwMS were randomized to receive either dalfampridine (10 mg twice daily) or a placebo for 2 weeks. Upper extremity function was assessed at baseline, after 1 week, after 2 weeks of treatment, and 2 weeks post-treatment using clinical tests (9-Hole Peg Test, Box, and Block Test, peak isometric grip force, 2-point discrimination) and self-reported questionnaires (disabilities of the arm, shoulder and hand, ability measure of the hand, Manual Ability Measurement 36). Data were analyzed using repeated-measures analysis of variance to evaluate group × time interactions. RESULTS: No significant group × time interactions were observed across clinical or self-reported outcomes. Both groups exhibited similar trends over time, with no measurable improvements in upper extremity dexterity, strength, or perceived function attributable to dalfampridine. CONCLUSION: Sustained-release dalfampridine does not appear to improve upper extremity function in pwMS, highlighting its limitations beyond gait-related benefits. These findings underscore the need for further research to explore alternative treatments targeting upper limb dysfunction in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02259361.