OBJECTIVE: To determine the safety of sustained-release 4-aminopyridine in subjects with mutiple sclerosis (MS) and to examine dose-related efficacy up to 40 mg twice daily. METHOD: Multicenter, randomized, double-blind, placebo-controlled, study. Following a 4-week baseline peroid, subjects were randomly assigned to receive Fampridine-SR (n=25, doses from 10 to 40 mg twice daily, increasing in 5 mg increments weekly) or placebo (n=11). A battery of assessments was performed weekly, including the MS Functional Composite (MSFC), fatigue questionnaires, and lower extremity manual muscle testing. RESULTS: The most common adverse events were dizziness, insomnia, paresthesia, asthenia, nausea, headache, and tremor. Five subjects were discontinued from Fampridine-SR because of adverse events at doses greater than 25 mg, and these included convulsions in two subjects at doses of 30 and 35 mg twice daily. Improvement were seen in lower extremity muscle strength (prospective analysis) and walking speed (post-hoc analysis) in the Fampridine-SR group compared to placebo (unadjusted p-values of 0.01 and 0.03, respectively). There were no significant differences in other MSFC measure or fatigue scores. CONCLUSIONS: Future studies should employ doses up to 20 mg twice daily with lower extremity strength and walking speed as potential outcome measures.