<p>According to the MS International Federation, the global prevalence of multiple sclerosis (MS) is increasing, although regional variations have been reported, which could provide valuable insights into MS pathophysiology. As we highlight in this Review, the prevalence of MS in Latin America is comparatively low, possibly owing at least in part to the unique genetic and environmental characteristics of this region. Latin America has experienced centuries of admixture between Native American Indian populations and people from other parts of the world, including Europe and — to a lesser extent — Africa. Moreover, certain environmental factors in the Southern Hemisphere might contribute to this reduced MS prevalence. The McDonald criteria are considered to be a useful tool to diagnose MS in Latin America, although it is important to exclude regional diseases that can mimic MS. MS research is burgeoning in the region, and increasing numbers of Latin American patients are participating in randomized clinical trials. In addition, real-world data from national and regional MS registries are helping us to understand the distinct features of the disease in Latin America.</p>