The long-term impact of interferon-beta-1b (IFN) might be improved by short-term immunosuppression with mitoxantrone (MITOX) in aggressive relapsing-remitting multiple sclerosis (ARMS) patients. In this 3-year clinical and MRI study, 109 ARMS patients (two or more relapses in the previous 12 months and one or more gadolinium (Gd)-enhancing MRI lesion) were randomised into two groups: 54 patients received MITOX monthly (12 mg/m(2); maximum 20 mg) combined with 1 g of methylprednisolone (MP) for 6 months followed by IFN for the last 27 months, and 55 patients received IFN for 3 years combined with 1 g of MP monthly for the first 6 months. The primary endpoint was the time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months. The time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months was delayed by 18 months in the MITOX group compared with the IFN group (p<0.012). The 3-year risk of worsening disability was reduced by 65% in the MITOX group relative to the IFN group (11.8% vs 33.6%). MITOX patients had a reduced relapse rate by 61.7%, a reduced number of Gd-enhancing lesions at month 9 and a slower accumulation of new T2 lesions at each time point. Although there were limitations in this investigator-academic-driven study, the data do suggest that mitoxantrone induction therapy prior to INF beta-1b may have a role in aggressive disease.