Background: Multiple sclerosis has both high healthcare and social impacts. Objective: The purpose of this article is to analyse the available literature describing the economic burden of multiple sclerosis and to compare costs among studies examining main cost drivers. Methods: A literature search on studies published in English on cost-of-illness of multiple sclerosis included in this review using PubMed, the Cochrane Library, SCOPUS and Web of Science includes a retrospective horizon and it describes direct and indirect costs in patients categorized into severity groups. Results: Several papers were obtained from the database search (n=37). Additionally, results from “hand searching” were also included, where a wider horizon was considered. Cost estimates were compared among studies that used a societal perspective on costs, time-period studied, and year of price level used. The estimated total annual cost per patient in Europe is on average 40,300€ (n=20). In addition, differences by geographic areas and severity groups are also considered. All in all, the higher the severity, the higher the associated costs. Conclusions: This systematic review provides one clear finding: multiple sclerosis places a huge economic burden on healthcare models and societies due to productivity losses and caregiver burden. Moreover, costs of drugs were main cost determinants for less severe cases of multiple sclerosis and informal care and production losses for the most severe cases of multiple sclerosis.