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Rural communities in the United States are far from monolithic and differ in critical ways that likely influence their vulnerability to opioid overdoses. This study combines data from multiple macro-level data sources, including the U.S. Census and CDC, to analyze fatal opioid overdoses across rural counties aggregated into six geographic distinct subregions: (1) Northeast, (2) Midwest, (3) South, (4) Southwest, (5) Mountain/Pacific, (6) Appalachia. Using county-level indicators related to structural disadvantage/despair, community health, and narcotic availability, this research employs several multivariate regression models to parse out key geographic variations in overdose predictors and patterns in rural America. Negative binomial regression findings indicate that while some predictors are consistent across geographic subregions marked differences also exist.