OBJECTIVES Multiple Sclerosis (MS), a demyelinating disease of the central nervous system, typically strikes adults during the primary productive time of their life. The physical and cognitive symptoms of MS can restrict individual's physical and economic activity resulting in a major financial burden on the patient, family, health system and society. This literature review was conducted to document the global economic burden of patients with MS. METHODS A review of the medical literature was conducted between January 1993 and August 2008 using the Medline, Embase, PsycInfo, HEED, and NHS-HEED databases. We included all studies written in the English language that reported any direct medical, direct non-medical, indirect, or intangible costs. RESULTS We identified 40 cost-of-illness studies which met the a priori inclusion criteria and represented the United States, Canada, Europe, Australia, and New Zealand. Costs associated with MS varied dramatically between countries. Comparing studies that reported consistent cost categories indicated that disease-modifying drugs constituted the most important direct cost category in Australia, Belgium, France, Germany, Italy, Spain, Switzerland, UK and the US. In the UK, informal care was also an important direct cost category and in Sweden frequent use of personal assistants was a driver of direct costs. Studies that adopted societal perspectives estimated larger indirect than direct costs. Productivity losses due to early retirement and time lost because of MS dominated the indirect costs. In general, the total cost of MS increased with disease severity. Both direct and indirect costs were higher overall for patients with SPMS vs. RRMS; however, these costs appeared to be related to level of disease severity rather than by type of MS. CONCLUSIONS Despite differences in country-specific factors, all studies included in this review showed that MS constitutes a major financial burden on the patient, caregiver, health system, and society.