BACKGROUND: Stigma directly contributes to physical, social, and psychic harm in people who use drugs. Current stigma frameworks privilege perspectives of stigmatizers, discounting the subjective lived experience of the stigmatized. Acknowledging that stigma is a universal phenomenon that manifests locally, we aimed to identify salient stigma-related attitudes, beliefs, behaviors, and experiences among people who use drugs in the rural Appalachian region of the United States. METHODS: Twenty-two people who use drugs residing in rural Ohio participated in qualitative interviews, sharing perspectives on and experiences with substance use stigma. Data were analyzed in three iterative rounds (using Rigorous and Accelerated Data Reduction, reflexive thematic analysis, in-vivo coding and analysis) then summarized in an experiential framework. RESULTS AND DISCUSSION: We organize and describe three salient facets of rural substance use stigma shared by participants: manifestations (stereotypes, prejudice, discrimination), outcomes (immediate reactions and personal consequences), and responses (adaptive and maladaptive coping styles). We discuss how these experiences are situated in cultural context and may be shaped by values like family, community, and self-reliance. CONCLUSION: Our study provides a conceptual framework for understanding the lived experience of substance use stigma in one sociocultural context. This framework has immediate utility for informing stigma reduction efforts in rural Appalachia and may be adapted to other contexts where the local character of stigma is of theoretical or practical import.