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Land use changes in suitable areas, habitat loss, and fragmentation are likely to be the most important consequences of climate change for wildlife populations. Yet, little is known about the response of large carnivores to climate change, globally and regionally. In this study, we utilized the ensemble modeling based on six species distribution models in order to predict the spatial vulnerability of the globally endangered Persian leopard (Panthera pardus saxicolor) to climate change in Chaharmahal and Bakhtiari Province, a semi-arid region in Iran. We showed that about 12.12 to 22.38% of leopard habitats in the area may be lost by 2050 due to climate change under four representative concentration pathways (RCPs) within the framework of two general circulation models (GCMs). In contrast, 1.87 to 13.01% of currently unsuitable habitats can become suitable with climate change. Overall, a considerable portion of the leopard range will remain intact under global warming, but still habitat loss to climate change will vary from 5.89 to 14.59%. Thus, large-scale but locally focused and flexible conservation strategies should be applied in intact and sensitive areas so that to prevent the intensification of anthropogenic threats such as overgrazing and forest degradation from collection of firewood, charcoal, and medicinal plants under changing climate.