Pre-exposure prophylaxis (PrEP) is a medication that prevents HIV acquisition, yet PrEP uptake has been low among people who inject drugs. Stigma has been identified as a fundamental driver of population health and may be a significant barrier to PrEP care engagement among PWID. However, there has been limited research on how stigma operates in rural and urban settings in relation to PrEP. Using in-depth semi-structured qualitative interviews (n = 57) we explore PrEP continuum engagement among people actively injecting drugs in rural and urban settings. Urban participants had more awareness and knowledge. Willingness to use PrEP was similar in both settings. However, no participant was currently using PrEP. Stigmas against drug use, HIV, and sexualities were identified as barriers to PrEP uptake, particularly in the rural setting. Syringe service programs in the urban setting were highlighted as a welcoming space where PWID could socialize and therefore mitigate stigma and foster information sharing.