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Ghanaians with perinatally acquired human immunodeficiency virus (HIV) infection now live into adulthood. It is known that adolescents and young adults living with HIV have a high risk of mental health comorbidity. Despite increasing global attention on HIV–mental health interactions, the field remains understudied in Ghana, with an attendant lack of national integrated care solutions. This study aimed to measure the burden and explore the context of depression, anxiety and stress symptoms among young people living with HIV receiving care at a tertiary care hospital in Ghana. This was an explanatory sequential mixed-methods study. Depression, anxiety and stress symptoms were measured using the Depression, Anxiety and Stress Scale, and their associations with quality of life (QoL), socioeconomic status, internalised stigma, disease stage and HIV-related risk-taking behaviours were explored. After preliminary quantitative data analysis, semi-structured interviews were conducted for those who screened positive for depression and/or anxiety to explore their experience with this comorbidity. This study found a low prevalence of depression and anxiety symptoms, which were associated with higher stigma scores and lower QoL. We believe this low prevalence to be attributable to the effect of several psychosocial interventional programmes, which were previously piloted with the study cohort that have gradually normalised mental health discussions. Participants also showed marked resilience and knowledge about their condition. The results of this study present an opportunity to advocate and scale up effective locally adapted and strength-based solutions to address the mental illness–HIV syndemic in Ghanaian young people living with HIV. [ABSTRACT FROM AUTHOR]