A randomized double-blind dose-titration crossover trial of the safety and efficacy of oral fampridine-SR (sustained release 4-aminopyridine) was conducted on spinal cord injured (SCI) patients at two centers. Twenty-six patients (n = 26) with incomplete lesions completed the trial. These patients all had chronic (>2 years) and stable neurological deficits. They received fampridine-SR 12.5 and 17.5 mg b.i.d. over a 2-week treatment period, followed by a 1-week washout and 2 weeks of placebo, or vice versa. Patients reported significant benefit of fampridine-SR over placebo on patient satisfaction (McNemar's test, p2 < 0.05) and quality of life scores (p2 < 0.01). Sensory scores (p1 < 0.01), including both pin prick (p1 = 0.059) and light touch (p1 = 0.058), and motor scores (adjusted to reflect only paretic segments) (p1 < 0.01) all yielded evidence of benefit of fampridine-SR over placebo. The Ashworth scale of spasticity was significantly (p2 < 0.05) reduced when patients received fampridine-SR. There were no statistically significant benefits of the drug on measures of pain or bowel, bladder and sexual function, or functional independence. Side effects of lightheadedness and nausea were transient and trivial relative to efficacy, and approximately 30% of patients reported a wish to continue to use fampridine-SR. The clinical benefits most likely derive from the K+ channel blocking action of the drug. Potassium channel blockade enhances axonal conduction across demyelinated internodes and enhances neuroneuronal and neuromuscular transmission in preserved axons. These results provide the first evidence of therapeutic benefit of fampridine-SR in SCI patients.