In recent years, the use of boosted protease inhibitors monotherapy has become increasingly important, especially considering the advantages in terms of costs, tolerability, and simplification. Despite that, knowledge about the efficacy and safety of this approach in HIV-1-infected adolescents who have acquired HIV-1 infection through perinatal transmission is still limited. We report here our experience with two adolescents who have been successfully treated with lopinavir/ritonavir monotherapy.