Pre-exposure prophylaxis (PrEP) is an effective but understudied tool for preventing HIV among women who inject drugs (WWID). This article is the first to explore WWID's rationale for PrEP initiation (or refusal) in a real-world setting. Purposive sampling was used to recruit 25 WWID, participating in a PrEP demonstration project operating within a syringe services program, based on whether they initiated or declined PrEP care. Content analysis of qualitative interviews was used to explore decisions to initiate PrEP (or not). We found that WWID view HIV as severe, perceive themselves to be susceptible to HIV, and believe PrEP is beneficial for HIV prevention. For some, however, real and perceived barriers outweighed benefits, leading to decisions not to initiate PrEP. Barriers included HIV stigma, fear of side effects, and needing assurance that PrEP care will be available long-term. Despite viewing PrEP as an important HIV prevention tool, not all WWID who were offered PrEP initiated it. For these women, supports to buffer perceived barriers to initiation and access to post-exposure prophylaxis may be warranted. For women who initiate, it is possible that adherence will wane if perceived risk does not remain high. Research to understand PrEP persistence is needed.