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We evaluated the effect of salvage antiretroviral therapy with lopinavir/ritonavir (LPV/r) on the immune system of heavily antiretroviral pretreated HIV-infected children. We carried out a longitudinal study in 20 antiretroviral experienced HIV-infected children to determine the changes in several immunological parameters (T cell subsets, thymic function) every 3 months during 18 months of follow-up on salvage therapy with LPV/r. Statistical analyses were performed with the Wilcoxon test, taking as a reference the basal value at the entry in the study. HIV-infected children showed an increase of CD4⁺T cells, a decrease in CD8⁺ T cells, and an increase in T cell rearrangement excision circle (TRECs) levels. The percentage of HIV children with undetectable viral load (VL ≤400 copies/ml) increased significantly (p = 0.007) and the percentage with SI viral phenotype decreased significantly (p = 0.002) at the end of the study. Thus, the viral phenotype changed to NSI/R5 after salvage therapy with LPV/r. Interestingly, we observed a significant decrease of memory (CD4⁺ CD45RO⁺) and a moderate decrease of activated (CD4⁺ HLA-DR⁺, CD4⁺ HLA-DR⁺CD38, CD4⁺ , CD45RO⁺HLA-DR⁺) CD4⁺ T cells during the follow-up. On the other hand, memory (CD8⁺ CD45RO⁺ and CD8⁺ CD45RO⁺CD38⁺ ), activated (CD8⁺ HLA-DR⁺CD38⁺ , CD8⁺ HLA-DR⁺, CD8⁺ CD38⁺ ), and effector (CD8⁺ CD57⁺, CD8⁺ CD28⁻CD57⁺) CD8⁺ T cells had a very significant decrease during follow-up. Our data indicate an immune system reconstitution in heavily pretreated HIV-infected children in response to salvage therapy with LPV/r as a consequence of a decrease in immune system activation and an increase in thymic function.