Neurocognitive impairment (NCI) and HIV risk are significant correlates of intent to use preexposure prophylaxis (PrEP). The extent to which similar outcomes could occur when these factors operate together, particularly for people who use drugs (PWUD), remains an important unanswered question. We therefore sought evidence that HIV risk behavior mediated the relationship between NCI and intent to use PrEP in high-risk PWUD in treatment. HIV-uninfected, methadone-maintained people who reported HIV-risk behaviors were enrolled (n = 400). Variables of interest (NCI, HIV risk behaviors, intent to use PrEP) were assessed using audio computer-assisted self-interview. We found preliminary evidence of indirect effect of HIV risk behaviors, such that NCI had an increased impact on intent to use PrEP via HIV risk behaviors. As a result of having this information, clinicians and researchers will be better equipped for evidence-informed targeting and dissemination efforts to optimize PrEP uptake by this underserved population.