There is not a standardized definition of rapidly worsening Multiple Sclerosis (MS). Arbitrary, we have designed under this term patients having a very active MS (patients having more than 2 relapses within the last 12 months) or rapid progression of handicap (more than 2 points EDSS progression within the last 12 months). The design of most previous studies using azathioprine, cyclophosphamide, methotrexate do not fulfill criteria to draw final conclusions as to the efficacy of these drugs as an immunoprophylactic agent in Multiple Sclerosis (MS). During the last five years, efficacy of immunomodulatory and immunosuppressive agents was provided by some well-designed randomized control clinical trials: among the immunosuppressors, mitoxantrone deserves special consideration as there were three controlled trials in Europe during the two last years that demonstrated strong efficacy both on clinical and MRI criteria. Due to its potentially cardiotoxicity, related to total cumulative dose, mitoxantrone should presently only be used in selected patients with a very high relapse rate and incomplete remission or in those who do not respond to INF beta treatment. The immunomodulatory agents (interferon beta 1a or 1b, copolymer 1) demonstrated a significant effect on the reduction of relapse rate (about 30 p. cent reduction), on progression of handicap and on MRI. In secondary progressive MS, an effect on progression is demonstrated only on patients still having relapses. No trial devoted to worsening patients as defined above have been yet designed with immunomodulatory agents.