Abstract. Pain is the clinical hallmark of sickle cell disease (SCD), yet pain management remains inadequate for many in this population due to lack of evidence-based pain treatment approaches for SCD, and due to stigma and implicit bias in the healthcare system. Black adolescents and young adults (AYAs, ages 16-30) with SCD are particularly vulnerable as they endure repeat hospitalizations due to pain crises while coping with stigma and related stressors, as well as the other challenges of transitioning to adulthood. Opioids are the primary agent used in chronic SCD pain management, despite evidence that they provide poor long-term relief and lead to negative physical and psychological consequences. Psychosocial interventions that teach cognitive and behavioral strategies can simultaneously reduce pain and stigma and enhance mood in patients with SCD. Cognitive behavioral therapy (CBT) is the primary behavioral health approach to managing pain in the general population, and digital CBT has expanded its accessibility. In SCD and other minority populations, we have demonstrated that a low-cost, scalable, technology-delivered version of CBT is feasible and can be effective for addressing stress and pain. We have learned that personalized support can improve engagement with digital CBT. We will now test a personalized approach customized for AYAs with SCD using peer support delivered through community-based organizations (CBOs). We will conduct a multisite, randomized controlled trial of digital CBT to understand the level of support needed to achieve benefits for reducing pain and stigma. Our Peer suppoRt for adolescents and Emerging adults with Sickle cell pain: promoting ENgagement in Cognitive behavioral thErapy (PRESENCE) study aims to reduce pain, opioid use, and healthcare utilization among AYAs with SCD. During the UG3 phase, we will leverage an established infrastructure for delivering virtual peer support interventions, existing digital CBT programs tailored by and for people with SCD, and partnerships with CBOs to jointly refine the study design, digital CBT content, and peer support component and work with the HEAL ERN CCC and DCC to prepare for the UH3 trial. After meeting UG3 milestones and transitioning to the UH3 phase, we will randomize 470 AYAs with frequent pain (³4 days/wk) over the past ³3 months to one of 3 treatment groups: 1) a digital CBT program with weekly one-on-one peer support provided via text and/or telephone based on participant preference (CBT+peer), 2) the same digital CBT program without peer support (self-guided CBT), or 3) usual care (UC). We first hypothesize that AYAs receiving either digital CBT treatment (CBT+ peer or self-guided CBT) will have better pain and mental health outcomes than AYAs receiving UC at 6 months. Second, we hypothesize that CBT+peer will be associated with improved program engagement and pain and mental health outcomes at 6 months compared with self-guided CBT. The PRESENCE trial will d...