Primary results of the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) 2002 trial showed that cognitive behavioural therapy (CBT) and medication management algorithm (MMA) (COMB-R) significantly improved depression in youth with HIV (YWH) compared with enhanced standard care (ESC). Acceptability and satisfaction were examined among study participants and clinicians. Between March 2017 and March 2019, 13 U.S. sites enrolled YWH, aged 12-24, diagnosed with nonpsychotic depression. Sites were randomised to either COMB-R (CBT by a therapist and licensed prescriber) or ESC (standard psychotherapy and medication management). After the intervention (week 24), participants, prescribers, and therapists rated acceptability and satisfaction. We compared site-level means using Wilcoxon tests. Both COMB-R ( = 69) and ESC ( = 71) participants had a mean age of 21.4 years, with 53% female, and 54% having acquired HIV perinatally. Baseline age, sex, depression levels, RNA viral load, and CD4 count were comparable between arms. The distribution of site-level mean participant acceptability was greater in COMB-R compared with ESC ( = 0.04). The distribution of site-level mean prescriber satisfaction was greater in COMB-R ( = 0.01). The was no evidence that the site-level mean therapist satisfaction did not differ between arms ( = 0.52). Acceptability and satisfaction for participants and licensed prescribers were higher at COMB-R sites compared with standard of care, indicating that this tailored, manual-guided, collaborative, measured care intervention was less burdensome in terms of the number of visits. Patient and medication provider satisfaction rates were higher than standard of care. While these results support the use of CBT and MMA in treating depression among YWH, further research is required to determine generalisability.