Hundreds of publications dealing with the prevalence of multiple sclerosis (MS) throughout the world exist, but little data have been published from South America. Epidemiological studies of MS vary according to environmental, racial and genetic factors; a better understanding of MS in South America would help us to elucidate the disease pattern in this population. The aim of this study is to review the evidence relevant to MS epidemiology in South America. We performed a systematic review of articles of MS epidemiology in South America, with special emphasis on those providing information on the incidence and prevalence of MS (population-based studies). Six papers provided information on MS epidemiology. One paper used the capture-recapture methodology, while the remainder employed traditional methods to collect the data. Population-based studies showed an MS prevalence rate ranging from 1.48 to 17 per 100 000 inhabitants. Available data suggest that the prevalence of MS is lower in South America than in developed countries. The reason for this observation is unknown. Some investigators suggest that certain environmental factors like sun exposure and vitamin D supplementation or the called ‘hygiene hypothesis’ may protect this population. Future studies will contribute to elucidate the etiology of that difference.