OBJECTIVES: To evaluate the effect of prolonged-release (PR) fampridine 10 mg tablet on generic quality of life (QoL) as measured by the EQ-5D in patients with multiple sclerosis (MS) with walking impairment. METHODS: The study population included 132 patients who enrolled in a 24-week randomized, double-blind, and placebo-controlled phase 2 trial (NCT01597297) of PR-fampridine 10 mg tablets or placebo twice daily in multiple sites in Europe and Canada. Patients were categorized into three groups: placebo, PR-fampridine responders (those with a mean improvement from baseline in the 12-item MS walking scale [MSWS-12] of ≥ 8 points over 24 weeks), and PR-fampridine nonresponders (those with worsening, no change, or <8 points improvement in MSWS-12). Changes from baseline were calculated for the EQ-5D utility index and visual analogue scale (VAS) by visit and over the 24 weeks. Within-group and pairwise comparisons were assessed based on the least square (LS) means using analysis of covariance (ANCOVA) models adjusting for baseline EQ-5D scores.  RESULTS: The placebo patients (n=64), responders (n=33), and nonresponders (n=35) were similar in baseline age, race, weight, and number of relapses in the past 1 and 2 years. The responders had higher mean baseline EQ-5D utility (0.56 vs. 0.51 and 0.52, respectively) and VAS (62.9 vs. 59.1 and 60.5, respectively) scores than the placebo patients and nonresponders. Over the 24 weeks, the EQ-5D utility score improved in the responders (mean change: 0.06, 95% CI: [0.01, 0.12]) but worsened in the placebo patients (mean change: -0.03, 95% CI: [-0.07, 0.01]) and nonresponders (mean change: -0.07, 95% CI: [-0.12, -0.02]). Similar trends were observed in the VAS scores although the differences within groups were generally not statistically significant.   CONCLUSIONS: PR-fampridine 10 mg tablets demonstrated significantly greater improvement in QoL among responders, despite starting from higher baseline EQ-5D scores, than the placebo or nonresponder groups.