BACKGROUND In a chronic disabling disorder such as multiple sclerosis (MS), adherence to treatment is of critical importance in maximizing benefits of therapy over the long term. Adverse events (AEs) are often cited by patients who discontinue therapy. METHODS Databases including Medline, CINAHL, and International Pharmaceutical Abstracts were searched for literature pertaining to adherence and AEs in MS published between January 1970 and August 2008. Clinical studies and case reports of AEs were included, as were papers that outlined factors that influence adherence. An advisory board with extensive experience in managing patients with MS developed guidelines to assist healthcare providers in maximizing adherence to disease-modifying therapy. DISCUSSION Internally based factors such as self-image, and externally based factors such as AEs, may influence patients' willingness and ability to adhere to therapy. Management of AEs associated with disease-modifying therapies and other therapies is reviewed, including intramuscular and subcutaneous interferon beta (IFNbeta)-1a, IFNbeta-1b, glatiramer acetate, natalizumab, methylprednisolone, mitoxantrone, cyclophosphamide, methotrexate, azathioprine, and intravenous immunoglobulin. CONCLUSIONS Effective management of MS is an ongoing, dynamic process that can enhance patients' adherence to therapy. Healthcare practitioners may address factors influencing adherence among patients with MS by managing treatment expectations, maintaining good communication with the patient, and managing AEs of treatment. Although the guidelines proposed herein originate from a single advisory board, it seems clear that by addressing patient concerns, healthcare practitioners can work with patients to enhance their ability to continue to adhere to their therapies and thereby gain the benefits of their treatment over the long term.