In Sub-Saharan Africa, increasing numbers of children with perinatally acquired HIV (PAHIV) are living into adolescence. These adolescents face numerous unique challenges such as parent illness/death and years of medication use. Optimizing care for these youth requires an understanding of the factors that contribute to physical health, psychological wellbeing, social relationships, and quality of life. This mixed methods study collected quantitative questionnaire data from 40 Ghanaian adolescents with PAHIV (50% female, 12–19 years old) who received care through an adolescent HIV clinic in Kumasi, Ghana. The study also presents results from qualitative interviews conducted with 20 adolescents. Results from quantitative analyses suggested that a significant number of participants were not virally suppressed (67%) and participants reported barriers to treatment adherence, limited social support, concerns about disclosure and HIV-related stigma, limited resources, and lower than expected quality of life (QOL). Salient themes from the qualitative analyses included limited understanding of how HIV is transmitted, the interplay between food insecurity and treatment adherence and the need for developing safe relationships through which adolescents can discuss their illness without fear of accidental disclosure of their HIV status.