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In the United States, HIV-infected children and adolescents are aging and using antiretroviral (ARV) therapy for extended periods of time.To assess trends in ARV use and long-term survival in an observational cohort of HIV-infected children and adolescents in the United States.The Pediatric Spectrum of HIV Disease Study (PSD) is a prospective chart review of more than 2000 HIV-infected children and adolescents. Patients were included in the analysis from enrollment until last follow-up.Triple-ARV therapy use (for 6 months or more) increased from 27% to 66% during 1997 to 2001 (P < 0.0001, χ2 for trend). The proportion of patients receiving 3 or more sequential triple-therapy regimens also increased from 4% to 17% during 1997 to 2001 (P < 0.0001, χ2 for trend), however, and the durability of triple-therapy regimens decreased from 13 to 7 months from the first to third regimen. Survival rates for the 1997 to 2001 birth cohorts were significantly better than for the 1989 to 1993 and 1994 to 1996 cohorts (P < 0.0001).Survival rates in the PSD cohort have increased in association with triple-ARV therapy use. With continued changes in ARV regimens, effective modifications in ARV therapy and the sustainability of gains in survival need to be determined.