Although more than 90% of youth perinatally infected with HIV live in sub-Saharan Africa, little is known about the psychosocial factors that impact their wellbeing, or how these youth cope with these challenges. The purpose of this study was to identify the psychosocial challenges and coping strategies among perinatal HIV-infected adolescents in Uganda. In-depth interviews were conducted with a purposive sample of 38 HIV-infected adolescents aged 12-19 years at a large HIV treatment center in Kampala. Data were analyzed thematically to identify themes and domains related to stressors and specific coping strategies. Psychosocial challenges included stigma/discrimination, relationship challenges such as HIV status disclosure, and medication difficulties. Coping strategies included medication adherence, concealment or limited disclosure of HIV status, treatment optimism, social support, rationalizing, social comparison, spirituality/religiosity, avoidance, and distraction. Age and gender differences also emerged: younger participants generally lacked specific coping strategies; compared to females, male adolescents reported greater use of avoidance/distraction techniques. Findings underscore the need to address stigma within homes and schools, and to equip adolescents with the comprehensive knowledge and skills to address their varied challenges.