Background: To date, HIV prevention efforts have largely relied on singular strategies (e.g., behavioral or bio-medical approach alone) with modest HIV risk reduction outcomes for people who use drugs (PWUD), many of whom experience a wide range of neurocognitive impairment (NCI). This study details the formative research process in preparation to develop an integrated bio-behavioral approach that incorporates innovative strategies to optimally address HIV prevention needs of high risk PWUD in drug treatment. Methods: Between May and June 2016, we conducted structured focus group sessions with treatment providers (n=10) and members of the target population (n=20) who were enrolled in methadone maintenance program in New Haven, Connecticut. Data analysis followed a thematic analysis approach utilizing several qualitative data analysis techniques, including inductive analysis and cross-case analysis. Results: Based on themes identified, we integrated the biomedical component – pre-exposure prophylaxis (PrEP) – into the adapted the evidence-based Community-friendly Health Recovery Program (CHRP) – a brief primary HIV prevention behavioral intervention – that incorporates innovative strategies to address NCI. This combination approach – now called CHRP-BB – is designed to address the HIV-related risk behaviors and PrEP uptake and adherence as experienced by many PWUD in treatment. Conclusion: The resultant brief evidence-based bio-behavioral approach could significantly advance primary prevention science by cost-effectively optimizing PrEP adherence and HIV risk reduction within common drug treatment settings.