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There is limited information on long-term consequences of continuing combination antiretroviral therapy (cART) consisting of <3 active drugs in treatment-experienced youth with perinatal HIV (PHIV). This study describes the clinical outcomes of PHIV youth who maintained virologic suppression (VS) for ≥1 year despite receiving cART with <3 active agents.A retrospective cohort study was conducted to quantify the duration of VS (viral load < 400 copies/mL), and using Cox proportional hazards regression, we identify factors associated with the primary outcome of virologic breakthrough (VB).Thirty-seven patients were included. The median age, baseline CD4 count and HIV RNA viral load were 14 years, 477 cells/mm3 and 2920 copies/mL, respectively. All patients harbored reverse transcriptase, and 57% harbored protease mutations. The median duration of VS was 37 months (interquartile range: 22–66). Fifteen patients (41%) had VB. The median change in CD4 count during VS was +82 cells/mm3 at 12 months. The risk of VB was lower in those who gained ≥50 cells/mm3 by 12 months (unadjusted hazards ratio: 0.271; 95% confidence interval: 0.0825–0.893; P, 0.032); however, this was not significant in the adjusted model.VS was maintained for a median of 3 years without decline in CD4 count. Independent risk factors for VB were not identified; however, there was a trend toward higher risk of VB in those without CD4 gain of ≥50 cells/mm3 by 12 months. Suppressive cART containing <3 active agents could be an option in difficult to manage PHIV youth with close monitoring.