Whereas previous studies have investigated correlates of extinction risk either at global or regional scales, our study explicitly models regional effects of anthropogenic threats and biological traits across the globe. Using phylogenetic comparative methods with a newly-updated supertree of 5020 extant mammals, we investigate the impact of species traits on extinction risk within each WWF ecoregion. Our analyses reveal strong geographical variation in the influence of traits on risk: notably, larger species are at higher risk only in tropical regions. We then relate these patterns to current and recent-historical human impacts across ecoregions using spatial modelling. The body–mass results apparently reflect historical declines of large species outside the tropics due to large-scale land conversion. Narrow-ranged and rare species tend to be at high risk in areas of high current human impacts. The interactions we describe between biological traits and anthropogenic threats increase understanding of the processes determining extinction risk.