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Background: One in four South Carolinians lives in a county along a nearly 200-mile stretch of Interstate 95 (I-95). Stretching from North Carolina to Georgia, this region is among the most rural, economically depressed, and racially/ethnically diverse in the state. Research is needed to identify social factors contributing to adverse health outcomes along the I-95 corridor, guide interventions, and establish a baseline for measuring progress. This study assessed social determinants of health in counties in South Carolina's I-95 corridor relative to the rest of the state. Method: Data for South Carolina's 46 counties were extracted from the Centers for Disease Control and Prevention Minority Health Social Vulnerability Index (SVI), which grouped 34 census variables into six themes: socioeconomic status, household composition and disability, minority status and language, housing type and transportation, health care infrastructure, and medical vulnerability. Each theme was ranked from 0 (least vulnerable) to 1 (most vulnerable). Measures between regions were compared using the Wilcoxon–Mann–Whitney test. Results: Compared with counties outside the I-95 corridor (n = 29), counties in the corridor (n = 17) scored higher on socioeconomic status vulnerability (.67 and.82, respectively) and medical vulnerability (.65 and.79, respectively). No statistically significant differences were found across other themes. Conclusion: Identifying social determinants of health in South Carolina's I-95 corridor is a crucial first step toward alleviating health disparities in this region. Interventions and policies should be developed in collaboration with local stakeholders to address distal social factors that create and reinforce health disparities. [ABSTRACT FROM AUTHOR]