The mammals are the biological group initially analysed by Wallace to define the Neotropical region (NR). Their areas of endemism (Ae) are considered historical patterns, which have been used to describe biogeographic schemes. However, the Ae at regional scale are currently unclear. In the present study, we analyse Ae of mammals at the regional scale and compare them with previous biogeographic schemes of the NR. The Ae of Neotropical terrestrial mammals were identified using the endemicity analysis (software NDM/VNDM). Our results showed that the NR is composed of 10 Ae, supported by 82 endemic taxa (6 families, 29 genera, and 47 species). The Ae showed a NR with multiple boundaries and with a core of higher overlap of the areas of endemism (OAE) from Veracruz and the Pacific coasts of Mexico to the southern limit of Amazonia in Brazil. The NR boundaries vary strikingly with latitude, with substantially more overlapping areas of endemism in the tropical biomes than in the temperate biomes of America. This pattern of OAE is consistent with the higher mammal-species richness zone within the tropical biomes and other biogeographic patterns such as higher productivity and spatial heterogeneity.