Adolescents and young adults (AYAs) receiving hematopoietic cell transplantation (HCT) are at high risk of poor psychosocial health. This study aimed to determine whether the Promoting Resilience in Stress Management (PRISM) intervention mitigated these risks during the first 6 months posttransplant. This multisite, parallel, randomized trial was conducted from April 2019 to March 2023. Eligible AYAs were aged 12-24 years, English speaking, and within 1 month of HCT for cancer or cancer predisposition syndrome. They were assigned 1:1 to PRISM (a brief, skills-based intervention targeting "resilience resources" [stress management, goal setting, cognitive reframing, and meaning making]) or usual care (UC). Outcomes included total symptoms of depression and anxiety (Hospital Anxiety and Depression Scale; primary outcome), hope (Snyder Hope Scale), resilience (10-item Connor-Davidson Resilience Scale), and health-related quality of life (HRQOL; Pediatric Quality of Life Inventory Cancer Module). Analyses leveraged multivariable linear regressions; exploratory analyses assessed the influence of baseline depression or anxiety. Of 94 enrolled and randomized AYAs, the mean age was 16.7 years (SD,4.2); 43 (46%) were female, 56 (60%) were non-Hispanic White, 22 (23%) were Hispanic, and nine (10%) were Black. Most (77%) had leukemia. Of n=50 randomized to PRISM and n=44 to UC, 37 (74%) and 33 (73%) completed all study procedures, respectively. In intention-to-treat analyses, PRISM did not affect 6-month depression and anxiety (β=-1.1; 95% CI, -3.7 to 1.5), hope (β=0.83; 95% CI, -3.3 to 4.9), resilience (β=-0.01; 95% CI, -3.0 to 3.0), or HRQOL (β=1.5; 95% CI, -4.7 to 7.9). Among AYAs with preexisting anxiety or depression, PRISM recipients reported greater 6-month improvements in hope (score change, +3.71; SD,6.9) versus UC recipients (score change, -2.76; SD,6.5) (p=.04). Resilience coaching did not influence outcomes in this sample. Exploratory findings suggest it may be more effective when directed toward those with concurrent distress.