Multiple sclerosis (MS) is a multifaceted disease in which genetic and environmental factors are involved. Although neurodegeneration aspect of MS has major influence in patients' disability, none of the available treatments have been shown to obviously reduce neurodegeneration. Recently, the role of Erythropoietin (EPO) as a neuroprotective and anti-inflammatory agent has been attracted tremendous interest. In the present randomized double-blind pilot study, we combined EPO with methylprednisolone (MPred) in severe motor relapsing-remitting MS (RR-MS) patients to target both inflammatory and neurodegenerative aspects of disease. Twenty patients with RR-MS in relapse phase were randomized into two groups. The case group (10 patients) received intravenous MPred (1,000 mg/24 h) and intravenous EPO (20,000 U/24 h) for five consecutive days, and the control group (10 patients) received just MPred at the same dose as the case group, and a placebo. Both groups were followed for 3 months by ambulatory index (AI), Expanded Disability Status Scale (EDSS) and by magnetic resonance imaging (MRI) parameters. Improvement in maximal distance walking, reflected by reduction in AI and EDSS, was observed in EPO group after second month and continued after 3 months. Furthermore, MRI data analysis showed significant reduction in the number of T2WI lesions in EPO group without any significant change in contrast enhancing and black hole lesions. There was no major side effect in EPO group. The results of this first therapeutic pilot trial in RR-MS patients are promising, but need to be validated in larger trials.