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Lyme disease is the most significant vector-borne disease in the United States, and its southward advance over several decades has been quantified. Previous research has examined the potential role of climate change on the disease’s expansion, but no studies have considered the role of future land cover upon its distribution. This research examines Lyme disease risk in the south-eastern U.S. based on projected land cover developed under four Intergovernmental Panel on Climate Change Scenarios: A1B, A2, B1, and B2. Land cover types and edge indices significantly associated with Lyme disease in Virginia were incorporated into a spatial Poisson regression model to quantify potential land cover suitability for Lyme disease in the south-eastern U.S. under each scenario. Our results indicate an intensification of potential land cover suitability for Lyme disease under the A scenarios and a decrease of potential land cover suitability under the B scenarios. The decrease under the B scenarios is a critical result, indicating that Lyme disease risk can be decreased by making different land cover choices. Additionally, health officials can focus efforts in projected high incidence areas.