BACKGROUNDPeople who use drugs (PWUD) have difficulty participating in clinical research. We evaluated approaches to engage PWUD in clinical research, using facilitated telemedicine for hepatitis C virus (HCV) care as an example.METHODSWe analyzed stakeholder interview transcripts and study-related data (i.e., progress reports, meeting minutes) from interrelated studies to understand engagement experiences at the patient, site, and organizational levels. Stakeholders include patient-participants, opioid treatment program (OTP) staff and administrators, and research team members involved in HCV management through facilitated telemedicine integrated into OTPs.RESULTSThree themes emerged. Initially, the research team sought understanding of the unique culture and community of each OTP (Theme 1). The team built trusting relationships through education, communication, and feedback (Theme 2). Finally, the research team enhanced collaborative care and incorporated the patients' voice to improve health outcomes (Theme 3). Patient-participants and OTP staff endorsed the integrated HCV care approach. Engagement practices are summarized as the CREATE framework (C = culture, R = respect, E = educate, A = advantage, T = trust, E = endorse).CONCLUSIONSPWUD engagement in clinical research is maximized by building trusting relationships with open communication channels. Understanding the community, demonstrating respect, and augmenting knowledge are foundational for engaging PWUD in clinical research. These practices are transferable to engagement of PWUD in clinical research broadly.