BACKGROUND First-line agents approved in the United States for treatment of relapsing multiple sclerosis (MS) include intramuscular interferon beta (IFNbeta)-1a, subcutaneous (SC) IFNbeta-1a, SC IFNbeta-1b, and SC glatiramer acetate. Intravenous mitoxantrone is the only agent approved for secondary progressive MS, progressive relapsing MS, and worsening relapsing MS. Intravenous natalizumab is approved for relapsing forms of MS generally in patients who have an inadequate response to, or are unable to tolerate, first-line therapies. Corticosteroids are commonly used to treat relapses. This paper reviews the incidence and management of common adverse events (AEs) associated with these treatments. METHODS MEDLINE and EMBASE were searched for clinical trials and other publications between 1985 and 2007 reporting AEs associated with MS therapies, using these search terms: multiple sclerosis, interferon, Avonex, Betaseron, Rebif, glatiramer, copolymer 1, Copaxone, mitoxantrone, natalizumab, adverse events. RESULTS A class-specific flu-like syndrome associated with IFNbeta can be managed through initial dose escalation and administration of analgesics and antipyretics, prophylactically or symptomatically. Injection-site reactions can occur in patients receiving injectable therapies, particularly SC IFNbeta or glatiramer acetate. The greatest risk to patients receiving mitoxantrone is cardiotoxicity; thus, the cumulative dose is limited. Allergic reactions occur rarely with natalizumab, and there is a potential risk of progressive multifocal leukoencephalopathy. AEs associated with short-term pulse corticosteroid therapy are usually transient and largely resolve after treatment is completed. CONCLUSIONS To improve adherence to therapy, it is important to educate patients regarding AEs and to manage AEs proactively.