The choice of an antiretroviral regimen can often impact on adherence, treatment satisfaction and therefore influence on clinical outcome. These concerns are particularly true in adolescents. In this setting, adherence is usually affected by multifactor events and biopsychosocial factors, which connect and changeover time. We evaluated the effect of a switch to a single-pill fixed-dose regimen on patient-reported outcomes, virologic and immunologic outcomes, and safety in a cohort of adolescents with perinatal HIV-1 infection. In addition, we evaluated the effect on low-level residual HIV-RNA. An open-label, non-randomised study was performed: 12 adolescents with a confirmed viremia <50 copies/mL treated with lamivudine or emtricitabine, tenofovir and efavirenz were switched to one-pill fixed-dose regimen of emtricitabine/tenofovir/efavirenz. At the end of follow-up, the new regimen was associated with improvements in treatment satisfaction, HIV-symptoms, whereas adherence remained high. No immunological or virological significative changes were observed. No side-effects were registered. Moreover, the low-level residual HIV-RNA was <3 copie/mL in all patients. One-pill fixed-dose regimen is an added value that favours adherence, reduces HIV-symptoms, improves patients' satisfaction and could better control of HIV-RNA in adolescents, too.