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Using the narratives of women who use(d) drugs, this account challenges popular understandings of Appalachia spread by such pundits as JD Vance by documenting how women, families, and communities cope with generational systems of oppression. Prescription opioids are associated with rising rates of overdose deaths and hepatitis C and HIV infection in the US, including in rural Central Appalachia. Yet there is a dearth of studies examining rural opioid use. RX Appalachia explores the gendered inequalities that situate women’s encounters with substance abuse treatment as well as additional state interventions targeted at women who use drugs in one of the most impoverished regions in the US.