The experience of hematopoietic cell transplantation (HCT) for hematologic malignancy among Adolescents and Young Adults (AYAs) is particularly difficult because age-related developmental challenges of identity, relationships, and vocation may add to the burden of cancer. Compared to other age-groups, AYAs have poorer psychosocial outcomes including increased anxiety and depression and poorer adherence to oral immunosuppressive medications. These outcomes may, in turn, predispose AYAs to disease-related morbidity and mortality such as graft-versus-host disease (GVHD) and/or cancer-relapse. A potential barrier to improving these experiences may be that AYAs have few opportunities to develop the personal resources needed to handle adversity. We have previously developed the “Promoting Resilience in Stress Management” (PRISM) intervention for AYAs with serious illness. This manualized, brief intervention is delivered in 4, 30-60 minute, one-on-one sessions, followed by a family meeting. It targets skills in stress-management and mindfulness, goal-setting, positive reframing, and meaning-making. All of these skills are associated with improved patient wellbeing in other populations, and preliminary findings from a recently closed pilot randomized controlled trial among AYAs with newly diagnosed cancer suggest PRISM is associated with improved health-related quality of life. This application proposes to build on our prior experience and fill a critical knowledge gap regarding PRISM’s impact among AYAs receiving HCT. Thus, we propose a multi-site randomized controlled trial among N=70 AYAs (n=35 PRISM and n=35 usual care; ages 12-24 years), with the primary trial outcome of patientreported symptoms of anxiety and depression. Secondary outcomes will include patient adherence to oral GVHD prophylaxis and the cost-effectiveness of the intervention in this population. We hypothesize that AYAs who receive PRISM will report fewer mixed affective symptoms and demonstrate better adherence. We also anticipate the intervention will be costeffective. In sum, this application offers an opportunity to expand the body of knowledge regarding methodologically rigorous and evidence-based psychosocial interventions and standards of care for AYAs with hematologic malignancies. Ultimately, this research has the potential to reduce the burden of cancer in these vulnerable populations.