BACKGROUND: In a recent trial, a 6-session intervention (BMT-CARE) integrating medical information with cognitive-behavioral strategies improved quality of life (QOL), mood, coping skills, and self-efficacy for family/friend caregivers of hematopoietic stem cell transplantation (HCT) recipients. This study examined whether improvements in coping and self-efficacy mediated the intervention effects on QOL and mood. METHODS: From December 2017 to April 2019, 100 caregivers of HCT recipients were enrolled into a randomized clinical trial of BMT-CARE versus usual care. Caregivers completed self-report measures of QOL (CareGiver Oncology Quality of Life questionnaire), depression and anxiety symptoms (Hospital Anxiety and Depression Scale), coping skills (Measure of Current Status), and self-efficacy (Cancer Self-Efficacy Scale-Transplant) at enrollment (before HCT) and 60 days after HCT. Causal mediation regression models were used to examine whether changes in coping and self-efficacy mediated intervention effects on QOL as well as depression and anxiety symptoms. RESULTS: Improvements in 60-day QOL in patients assigned to BMT-CARE were partially mediated by improved coping and self-efficacy (indirect effect, 6.93; SE, 1.85; 95% CI, 3.71-11.05). Similarly, reductions in 60-day depression and anxiety symptoms were partially mediated by improved coping and self-efficacy (indirect effect for depression, −1.19; SE, 0.42; 95% CI, −2.23 to −0.53; indirect effect for anxiety, −1.46; SE, 0.55; 95% CI, −2.52 to −0.43). Combined improvements in coping and selfefficacy accounted for 67%, 80%, and 39% of the total intervention effects on QOL and depression and anxiety symptoms, respectively. CONCLUSIONS: Coping and self-efficacy are essential components of a brief psychosocial intervention that improves QOL and mood for caregivers of HCT recipients during the acute recovery period.