Background: A brief multimodal psychosocial intervention (BMT-CARE) for caregivers of HCT recipients demonstrated promising efficacy for improving caregiver quality of life (QOL), mood, coping skills, and self-efficacy. We examined whether improvements in coping and self-efficacy mediated the intervention effects on QOL and mood. Methods: We conducted a randomized clinical trial of BMT-CARE for caregivers of patients undergoing autologous or allogeneic HCT at a single institution. Caregivers were randomly assigned to BMT-CARE or usual care. BMT-CARE was tailored to the HCT trajectory and integrated treatment-related education and self-care with cognitive-behavioral skills and caregiving-specific strategies to promote coping. Caregivers completed self-report measures of QOL (CareGiver Oncology QOL), 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 and 60 days post-HCT. We used causal mediation regression models to examine whether changes in coping and self-efficacy mediated intervention effects on QOL, depression and anxiety symptoms. Results: Caregivers randomized to BMT-CARE reported improved self-efficacy (adjusted means: 156.20 vs. 147.06, P=0.023) and coping skills (adjusted means: 36.54 vs. 25.41, P<0.001). Improved coping and self-efficacy partially mediated the intervention effects on 60-day QOL (indirect effect=6.93, SE=1.85, 95% CI [3.71, 11.05]). Similarly, improved coping and self-efficacy partially mediated reductions in 60-day depression and anxiety symptoms (indirect effect depression=-1.19, SE=0.42, 95% CI [-2.23, -0.53]; indirect effect anxiety=-1.46, SE=0.55, 95% CI [-2.52, -0.43]). Combined improvements in coping and self-efficacy accounted for 67%, 80%, and 39% of the total intervention effect on QOL and depression and anxiety symptoms, respectively. Conclusions: A brief multimodal intervention for caregivers of HCT recipients may improve QOL and mood by enhancing coping skills and self-efficacy. These findings offer important insights into the mechanisms by which caregiver-directed interventions may enhance caregiver QOL and reduce their psychological distress.