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Lopinavir/ritonavir (LPV/r) is now the protease inhibitor regimen of choice in the first-line antiretroviral therapy for children <6 years of age.We included all the human immunodeficiency virus (HIV) type 1-infected highly active antiretroviral therapy (HAART)-naive children who started an LPV/r-based regimen between 2000 and 2009 at the Necker Hospital (Paris, France). Virologic failure (VF) was defined as an HIV-RNA ≥50 copies/mL. Resistance genotypic test was performed in case of VF.A total of 43 children were included at a median age of 4.8 years (1.8–8.0). Median level of HIV RNA and percentage of CD4 cell count was 5.5 log10 copies/mL (4.6–6) and 15% (8–27.5), respectively. HAART included LPV/r and 2 nucleoside reverse-transcriptase inhibitors, mainly lamivudine (3TC), zidovudine, and/or abacavir. The median follow-up period was 36 months (18–72). Less than 50 copies/mL of HIV RNA was observed in 46%, 67%, and 70% of the children at months 6, 9, and 12, respectively. In all, 20 children (46.5%) experienced a VF. The risk factors of primary VF were a young age and a low socioeconomic status. The genotypic resistance test, performed for 18 of 20 children with VF, revealed 1 LPV/r-resistant virus and protease inhibitor-related major mutations without LPV/r resistance in 2 other children. Of the 18 children with VF, 15 received a 3TC-based HAART: 12 of 15 (80%) harbored a 3TC-resistant virus. No virus resistant to zidovudine or abacavir was found.In all, 70% of HAART-naive children had virologic success at month 12. The selection of LPV-resistant strains was a rare event. A high rate of selection of 3TC-mutations strengthens the recommendation to prefer a first-line 3TC-sparing regimen, particularly for children with risk factors of poor adherence.