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The evolution of the HIV-specific CD8⁺ T cell response in patients receiving potent combination therapy has been well documented in adult patients. However, no study reported whether baseline HIV-specific CD8⁺ T cell response is linked to treatment outcome. The aims of this study were to investigate both the impact of baseline memory cytotoxic T lymphocytes (CTL) on treatment outcome and the effect of potent therapy on memory HIV-specific CTL in HIV-1-infected pediatric patients. The study group comprised 30 children who started a first-line combination treatment including at least three drugs from two different classes and were longitudinally followed during treatment. Their memory HIV-specific responses were measured at baseline and during treatment, as well as their plasma viremia and CD4⁺ levels. The intensity of memory Gag-specific CTL and the breadth of the CTL response at the beginning of treatment were significantly correlated with lower plasma viral load during treatment, independently of baseline plasma viral load, CD4⁺ counts, and age. Children with partially controlled viral replication had enhanced Gag-specific CTL compared to their baseline value. This improvement of antiviral responses during treatment was not observed when viral replication was either fully suppressed or uncontrolled. In conclusion, our results show that higher baseline HIV-specific CTL are linked to lower viremia under combination therapy. This result adds further support to the hypothesis that cooperation between the antiviral immune response and antiviral drugs could be helpful for therapeutic management of HIV-infected patients.