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Context: The guanaco (Lama guanicoe) is one of the four species of South American camels, and is the largest native mammal inhabiting arid and semi-arid environments in South America. Although the guanaco was abundant and widely distributed in the past, currently its density and distribution range are substantially reduced, inhabiting mainly Southern Patagonia in small isolated groups. The decline in guanaco populations is most likely related to the Anthropocene defaunation process that is affecting large mammals in developing countries worldwide, but the extent and causes of these changes are not well understood. Aims: To explore both the changes in the distribution of guanaco populations in Northwest Patagonia and the environmental and anthropic factors that shaped the distribution patterns, by employing a long-term perspective spanning from the end of the Late Holocene to present times (i.e. the last 2500 years). Methods: We combine archaeological information, ethnohistorical records and current observations and apply Species Distribution Models using bioclimatic and anthropic factors as explanatory variables. Key results: Guanaco spatial distribution in Northwest Patagonia changed significantly throughout time. This change consisted in the displacement of the species towards the east of the region and its disappearance from northwest Neuquén and southwest Mendoza in the last 30 years. In particular, the high-density urban settlements and roads, and secondly, competition with ovicaprine livestock (goats and sheep) for forage are the main factors explaining the change in guanaco distribution. Conclusions: Guanaco and human populations co-existed in the same areas during the Late Holocene and historic times (16th to 19th centuries), but during the 20th century the modern anthropic impact generated a spatial dissociation between both species, pushing guanaco populations to drier and more unproductive areas that were previously peripheral in its distribution. Implications: As with many other large mammal species in developing countries, Northwest Patagonia guanaco populations are undergoing significant changes in their range due to modern anthropic activities. Considering that these events are directly related to population declines and extirpations, together with the striking low density recorded for Northwest Patagonia guanaco populations, urgent management actions are needed to mitigate current human impacts. The guanaco is the largest native mammal inhabiting arid and semi-arid South American environments, with current density and distribution ranges substantially reduced. Combined lines of evidence model how and why distribution changed in the last 2500 years in Northwest Patagonia, showing guanaco populations pushed to drier, unproductive areas of the east by recent urbanization and livestock practices. Like large mammals in developing countries worldwide, guanacos are threatened by modern human activities, so urgent measures are needed to mitigate impacts. Image by Bruno F. Moscardi and S. Ivan Perez. [ABSTRACT FROM AUTHOR]