Background: A high percentage of patients with multiple sclerosis present cognitive alterations. Because 4-aminopyridine improves nerve conduction and efficient synaptic connection could improve cognitive dysfunction. Objective: To evaluate the efficacy on cognitive performance and safety of 4-aminopyridine administered to patients with relapsing-remitting multiple sclerosis. Methods: A randomized, double-blind, placebo controlled clinical trial was conducted in patients with relapsing-remitting multiple sclerosis diagnosis according to the McDonald criteria. At the beginning and at the end of the treatment different tests were used to assess cognitive performance. Subsequently, patients were randomized 1:1 to receive treatment or placebo. A bootstrap-t test was proposed to test the effectiveness of cognitive performance, considering a p-value < 0.05 as statistically significant. Results: Twenty-four patients were recruited of which 21 completed the trial, 11 with 4-aminopyridine and 10 with placebo treatment. No significant differences between groups in the initial assessments were observed. In terms of efficacy, the experimental group achieved significantly higher scores in attention span, verbal fluency, planning and graphics and constructive motion. Conclusions: 4-aminopyridine proved to be an effective treatment on cognitive aspects in patients with relapsing-remitting multiple sclerosis. Drug doses were shown to be safe with mild to moderate adverse events (ClinicalTrials.gov number, NCT02280096).