Rural communities in the US have increasing HIV burden tied to injection drug use, yet engagement in pre-exposure prophylaxis (PrEP) care has been low among people who inject drugs (PWID). Syringe service programs (SSPs) are widely implemented in Kentucky's Appalachian region, presenting an important opportunity to scale PrEP services. This paper examines PrEP awareness, interest and preferences among PWID attending community-based SSPs in Appalachia. Eighty participants were enrolled from two SSP locations. Eligibility included: ≥ 18 years old, current injection drug use and SSP use, and an indication for PrEP as defined by CDC guidelines. Participants completed a structured baseline interview. Predictors of PrEP awareness, interest and formulation preferences were examined. 38.8% reported baseline awareness of PrEP, 50% expressed high interest in PrEP, and 48.1%reported a preference for injectable PrEP. Significant bivariate predictors of PrEP interest included: current worry about health, higher perceived HIV risk, higher community HIV stigma, and higher enacted substance use stigma in the past year; in the adjusted model, enacted substance use stigma remained significant. Findings demonstrate substantial interest in PrEP among rural PWID. Intrapersonal and social determinant factors were associated with PrEP interest, which suggests the importance of multi-level intervention targets to increase PrEP uptake.