Early highly active antiretroviral therapy is recommended in all vertically human immunodeficiency virus (HIV)-infected infants. We describe the long-term immunologic outcome after planned treatment interruption (PTI) in 7 children diagnosed and treated during acute HIV infection (age <12 weeks). Children had remained a median of 57 months off treatment, 3 of them indefinitely. The 2 patients with the lowest nadir CD4% reinitiated highly active antiretroviral therapy because of a CD4 cell decline of <20%; 2 children resumed treatment because of clinical progression and parents' wishes. All patients experienced a decrease in CD4% after PTI, which particularly affected the naive subpopulation. The interferon-γ response against HIV-p24 antigen directly correlated with nadir CD4%. Our results suggest that early treatment in HIV-infected infants increases their potential to safely control viral replication after PTI for long periods.