Identifying the factors determining the non-native species richness (NNSR) in a given area is essential for preventing species invasions. The relative importance of human-related and natural factors considered for explaining NNSR might depend upon both the spatial scale (i.e. the extent of the gradients sampled) and the historical context of the area surveyed. Here, using a worldwide database of freshwater fish occurrences, we tested whether the relative influence of human and ecological determinants of non-native fish species establishment at the scale of the biogeographic realm was consistent (i) with that observed worldwide, and (ii) among the different biogeographical realms. The prominent role of human activity in shaping the global (i.e. worldwide) pattern of NNSR cannot be directly extrapolated to the biogeographic realms. Furthermore, the relationships between human and ecological determinants and NNSR vary strikingly across biogeographic realms, revealing a strong context dependency of the determinants of NNSR. In particular, the human-related factors play a predominant role in explaining the establishment of non-native species in economically developed realms, while in the other realms environmental characteristics of the river basins best explained geographical patterns of NNSR. In the face of future biological invasions, considering both the spatial scale and the historical context of the surveyed area is crucial to adopt effective conservation strategies.