Abstract Aim Topography is a fundamental geophysical observable that contains valuable information about the geodynamic, tectonic and climatic history of a region. Here, we extend the traditional uses of topographic analysis to evaluate the role played by topography in the distribution of regional-scale biodiversity in the south-western USA. An important aspect of our study is its ability to provide a way to quantify characteristics of the topographic fabric and to construct predictive models that can be used to test hypotheses that relate topography and biodiversity. Location South-western USA region of the North American Cordillera. Methods Our approach begins with a quantitative analysis of the topography and the construction of a predicted biodiversity map based on measurable topographic quantities: organization, roughness, slope aspect, grain orientation and mean elevation. We then make a quantitative comparison between the predicted and observed biodiversity, based on the assumption that land-cover diversity is a plausible measure of regional-scale biodiversity. Land-cover information used for this study was collected as part of the U.S.G.S. global land cover characteristics (GLCC) project and is derived from satellite (AVHRR) imagery. Results To a first order, the predicted regional-scale biodiversity based on our topographic model shows a good correlation with the observed biodiversity (as estimated from the land-cover diversity). Our model overestimates the biodiversity in many parts of the Colorado Plateau, Rio Grande Rift, and the low desert regions of the Southern Basin and Range, suggesting that in these provinces a biodiversity estimate based solely on topography is an over-simplification. However, much of the Madrean Archipelago and Sierra Madre provinces, which are centres of high biodiversity in this region, show excellent agreement between the observed and predicted biodiversity. Main conclusions While we acknowledge that many other factors in addition to topography have an important influence on biodiversity (particularly on a local scale), we conclude that topography plays a primary role in the regional to continental-scale biodiversity, particularly in regions characterized by insular mountain fabrics.