Background.To assess tolerance and efficacy of early multitherapy including a protease inhibitor for infants perinatally infected with HIV.Methods.Observational study of tolerance and clinical and immunovirologic evolution in HIV-infected infants treated before the age of 1 year in the French Perinatal Study.Results.Thirty-one infants were included. The median age was 3.7 months at initiation of multitherapy. Clinical stage was C (n= 8), B (n= 5) or A/N (n= 18). The median HIV RNA viral load was 5.8 log copies/ml, and the median CD4 cell percentage was 29%. Median follow-up of treatment was 27 months. Of 31 infants 15 experienced mild to moderate adverse events. No infant had clinical or immunologic progression. The median change in viral load was −2.7 log copies/ml after 3 months, −2.0 log after 12 months and −1.7 log after 24 months of treatment. The proportion of infants with a viral load below 500 copies/ml decreased from 53% at 6 months to 18% at 24 months of treatment. The virologic response was not correlated with viral load at baseline. However, the slope of the viral load decrease during the first month of treatment was predictive of the virologic response at 3 and 6 months. Fourteen infants with a viral load of >500 copies/ml after 6 months of treatment displayed viruses with antiretroviral resistance mutations in reverse transcriptase and/or protease genes.Conclusions.Despite the absence of clinical or immunologic progression, the high frequency of virologic failure associated with genotypic resistance reveals the difficulties associated with implementing antiretroviral multitherapy in infants. Suboptimal doses of protease inhibitor could be a factor contributing to treatment failure.