Interferons beta have shown some positive effects on cognitive function in multiple sclerosis (MS). The potential immunosuppressive impact of mitoxantrone on cognitive dysfunction in MS has never been evaluated. We assessed changes in cognitive dysfunction in patients with very active MS treated with mitoxantrone combined with methylprednisolone. We assessed a non randomized controlled trial including successively 15 consecutive MS patients. Very active MS was defined by a progression of at least two EDSS points or more than two relapses during the previous year and at least one enhanced lesion after gadolinium infusion on MRI. All patients received a monthly intravenous pulse of mitoxantrone (20mg) for six months with methylprednisolone (1g). Global cognitive efficiency, memory and executive function were assessed before treatment (M0) and after six months (M6) and 12 months (M12) of treatment. To evaluate the learning effect, 15 healthy subjects also participated. A significant improvement in global cognitive efficiency was observed at M6 and was sustained at M12, as a few parameters on memory and executive functions. We suggest that mitoxantrone combined with methylprednisolone has a potential positive effect on cognitive functions.