BACKGROUND: Intersectional stigma of drug-use and HIV hinders provision and utilization of HIV prevention services for people who inject drugs (PWID), particularly within rural US communities. Resilience and coping may be critical for PWID to counter pervasive stigma. METHODS: Between October 2021 and July 2022, 35 in-depth interviews were conducted in Appalachian Ohio to understand the intersection of drug-use and HIV prevention stigma and how resilience and coping processes are displayed, shared, and enacted. Interviews were audio-recorded and transcribed verbatim. Thematic analysis was conducted, guided by Harper et al.'s four key resilience processes: (a) engaging in health-promoting cognitive processes, (b) enacting in health behavioral practices, (c) exchanging social support, and (d) empowering other PWID to engage in health behavior practices. RESULTS: Resilience processes aligned with the Harper framework with additional coping processes identified, including anticipation strategies and maladaptive coping. Empowering other PWID emerged as a prominent resiliency process, often supported by systems of support like syringe service programs (SSPs), which provided resources and helped reduce stigma. However, bidirectional social support was constrained, as PWID frequently acted as providers of resources and referrals for peers despite limited knowledge of HIV prevention strategies and feeling unsupported themselves. Anticipation strategies were employed to manage anticipated stigma, including accessing support or, conversely, avoiding healthcare and refraining from disclosing drug use. Maladaptive coping included behaviors such as social isolation and self-administered medical care, highlighting critical gaps in opportunities to foster resilience. CONCLUSIONS: Findings highlight that empowering peers and anticipation strategies can be key resilience processes, while maladaptive coping and limited bidirectional social support underscore the need for resilience-building and stigma-reduction interventions. Tailored systems of support for PWID in rural communities are critical to fostering adaptive coping and enhancing engagement with HIV prevention services.