PrEP is an HIV prevention option that could benefit substance-involved women, a high-risk population with low PrEP uptake. Little is known about their interest in PrEP. This qualitative study used in-depth interviews to examine PrEP willingness, barriers, and facilitators among 16 women in outpatient psychosocial substance use treatment, methadone, and/or harm reduction/syringe programs in NYC. All expressed willingness to use PrEP, but only during periods of perceived risk. Women perceived themselves to be at high risk for HIV when engaging in active substance use and/or transactional sex. They perceived themselves to be at low risk and therefore unmotivated to take PrEP when abstinent from these activities. Paradoxically, a major barrier to using PrEP was anticipated interference from substance use and transactional sex, the very same activities that create a perception of risk. Facilitators of PrEP use included perceptions of it as effortless (as opposed to barrier methods during sex) and effective, safe, and accessible. Other barriers included fear of stigma and doubts about adhering daily. Recommendations for best PrEP implementation practices for substance-involved women included tailored and venue-specific PrEP information and messaging, PrEP discussion with trusted medical providers, and on-site PrEP prescription in substance use treatment and harm reduction programs.