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Many infectious disease forecasting models in the United States (US) are built with data partitioned into geopolitical regions centered on human activity as opposed to regions defined by natural ecosystems; although useful for data collection and intervention, this has the potential to mask biological relationships between the environment and disease. We explored this concept by analyzing the correlations between climate and West Nile virus (WNV) case data aggregated to geopolitical and ecological regions. We compared correlations between minimum, maximum, and mean annual temperature; precipitation; and annual WNV neuroinvasive disease (WNND) case data from 2005 to 2019 when partitioned into (a) climate regions defined by the National Oceanic and Atmospheric Administration (NOAA) and (b) Level I ecoregions defined by the Environmental Protection Agency (EPA). We found that correlations between climate and WNND in NOAA climate regions and EPA ecoregions were often contradictory in both direction and magnitude, with EPA ecoregions more often supporting previously established biological hypotheses and environmental dynamics underlying vector‐borne disease transmission. Using ecological regions to examine the relationships between climate and disease cases can enhance the predictive power of forecasts at various scales, motivating a conceptual shift in large‐scale analyses from geopolitical frameworks to more ecologically meaningful regions. Plain Language Summary: In the United States (US), geopolitical subdivisions like states and counties are the governing regions that collect public health data and implement health interventions like risk messaging, mask mandates, or spraying chemicals for mosquito control. These subdivisions were mostly decided by politics and other human activity, not similarities in ecosystems and climate. This can make it difficult to understand how climate affects illnesses like mosquito‐borne disease since mosquitoes will live within specific ecosystems and aren't confined to geopolitical boundaries as health data are. We explored this idea by analyzing the relationships between temperature, precipitation, and the mosquito‐borne pathogen called West Nile virus (WNV) from 2005 to 2019. We grouped our data using two different regional boundaries: (a) climate regions from the National Oceanic and Atmospheric Administration (NOAA), primarily based on state boundaries, and (b) ecoregions from the Environmental Protection Agency (EPA), based on similar ecosystems. We found that these groupings resulted in some contradictory results. The results using EPA ecoregions more often agreed with biological hypotheses, so it may be a better approach to dividing the US for similar studies. We encourage other scientists to consider this conceptual shift from analyzing data by geopolitical boundaries to more ecologically meaningful regions. Key Points: While health data is collected within geopolitical boundaries, environmental disease dynamics are influenced by ecosystem characteristicsFor West Nile virus, correlations between cases and climate were different depending on geopolitical or ecosystem regional groupings of dataWe propose a conceptual shift from analyzing climate and health data at geopolitical boundaries to more ecologically meaningful regions [ABSTRACT FROM AUTHOR]