Objective: There is only limited evidence from adequately controlled clinical trials to support high-dose methylprednisolone therapy for attacks of multiple sclerosis (MS) and none supporting oral administration. We assessed the effect of oral high-dose methylprednisolone therapy in attacks of MS.Methods: Twenty-five patients with an attack of MS lasting less than 4 weeks were randomized to placebo treatment. Twenty-six patients received oral methylprednisolone (500 mg once a day for 5 days with a 10-day tapering period). The patients received scores on the Scripps Neurological Rating Scale (NRS) and Kurtzke Expanded Disability Status Scale. The symptoms were scored on a visual analog scale (VAS) before treatment and after 1, 3, and 8 weeks of treatment. Primary efficacy measures were NRS and VAS scores in the first 3 weeks and changes in NRS score and answers to an efficacy questionnaire administered after 8 weeks of treatment.Results: Changes in NRS scores among methylprednisolone- and placebo-treated patients differed significantly in the first 3 weeks and after 8 weeks(p = 0.005 and p = 0.0007). VAS scores the first 3 weeks and treatment efficacy after 8 weeks also favored a beneficial effect of methylprednisolone treatment (p = 0.02 and p = 0.05). After 1, 3, and 8 weeks, 4%, 24%, and 32% in the placebo group and 31%, 54%, and 65% in the methylprednisolone group had improved one point on the Expanded Disability Status Scale score (all p < 0.05). No serious adverse events were seen.Conclusion: Oral high-dose methylprednisolone is recommended for managing attacks of MS.