Treatment of advanced forms of MS is more difficult than relapsing-remitting MS. A wide range of medications have been used to try to slow the progression of the disease, with results that have been at best fair.

Mitoxantrone has shown positive effects in patients with a secondary progressive and progressive relapsing courses. It is moderately effective in reducing the progression of the disease and the frequency of relapses in patients in short-term follow-up. In 2007 it was the only medication approved in the USA for both secondary progressive and progressive relapsing multiple sclerosis; however, it causes dose-dependent cardiac toxicity which limits its long-term use. It is also not approved in Europe.

Natalizumab or Tysabri has shown efficacy and has been approved for secondary progressive MS with relapses.

Interferon-beta-1b (Betaseron or Betaferon) slowed progression of the disease in one clinical trial for secondary progressive MS, but not in another. However, both studies demonstrated that interferon recipients had fewer relapses and less disease activity, as assessed by magnetic resonance imaging (MRI). Therefore, interferons show promise in treating secondary progressive MS, but more data is needed to support their widespread use.