Background. Considerable uncertainty remains as to whether early initiation of antiretroviral therapy (ART) in children with vertically acquired human immunodeficiency virus (HIV) infection increases the benefit in terms of immunological response. Methods. The association between immunological outcome and early initiation of and/or more-potent ART was investigated, using age-standardized z scores for CD4 cell counts (hereafter, "CD4 z scores"), in 131 HIV-infected children enrolled in the European Collaborative Study, a birth cohort study. Results. Median age at initiation of the most-potent ART was 4 years (range, 0.1-15.5 years). Initiation of treatment after 5 months of age resulted in nonsignificantly lower CD4 z scores 6 months after initiation. Time to a 20% increase in CD4 z score was associated with age at initiation of the most-potent ART (adjusted hazard ratios [AHRs], 0.37 [P<.01] and 0.43 [P = .05] for 5 months-5 years of age and >5 years of age, respectively, compared with <5 months of age), ethnicity (AHR, 0.48 [P = .01], for black vs. white), and highly active ART (HAART) with or without prior ART (AHRs, 3.16 [P<.01] and 3.95 [P<.001], vs. mono or dual ART, respectively). The risk of subsequent deterioration of CD4 z score was similar for children who initiated ART in different age groups (χ2 = 0.824; P = .82). Conclusions. We confirm the effectiveness of HAART with respect to the recovery of CD4 cell count and suggest a benefit of initiating ART before the age of 5 months. Age at initiation of the most-potent ART was not associated with the likelihood of sustaining the recovery of CD4 cell count. © 2006 by the Infectious Diseases Society of America. All rights reserved.