IMPORTANCE: As perinatally human immunodeficiency virus-infected youth (PHIVY) in the United States grow older and more treatment experienced, clinicians need updated information about the association of age, CD4 cell count, viral load (VL), and antiretroviral (ARV) drug use with risk of opportunistic infections, key clinical events, and mortality to understand patient risks and improve care. OBJECTIVE: To examine the incidence or first occurrence during follow-up of key clinical events (including Centers for Disease Control and Prevention stage B [CDC-B] and stage C [CDC-C] events) and mortality among PHIVY stratified by age, CD4 cell count, and VL and ARV status. DESIGN, SETTING, AND PARTICIPANTS: Combining data from the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol and International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1074 multicenter cohort studies (March 2007 through April 2015), we estimated event rates during person-time spent in key strata of age (7-12, 13-17, and 18-30 years), CD4 cell count (<200, 200-499, and ≥500/μL), and a combined measure of VL and ARV status (VL <400 or ≥400 copies/mL; ARV therapy or no ARV therapy). A total of 1562 participants in the PHACS Adolescent Master Protocol and IMPAACT P1074 were eligible, and 1446 PHIVY from 41 ambulatory sites in the 12 US states, including Puerto Rico were enrolled. The dates of analysis were March 2015 through January 2017. MAIN OUTCOMES AND MEASURES: Clinical event rates stratified by person-time in age, CD4 cell count, and VL and ARV categories. RESULTS: A total of 1446 PHIVY participated in the study (mean [SD] age, 14.6 [4.6] years; 759 female [52.5%]; 953 black [65.9%]). During a mean (SD) follow-up of 4.9 (1.3) years, higher incidences of CDC-B events, CDC-C events, and mortality were observed as participants aged. Older PHIVY (aged 13-17 and 18-30 years) spent more time with a VL of 400 copies/mL or more and with a CD4 cell count of less than 200/µL compared with 7- to 12-year-old participants (30% and 44% vs 22% of person-time with a VL≥400 copies/mL; 5% and 18% vs 2% of person-time with CD4 cell count <200/µL; P < .001 for each comparison). We observed higher rates of CDC-B events, CDC-C events, bacterial infections, and mortality at lower CD4 cell counts, as expected. The mortality rate among older PHIVY was 6 to 12 times that among the general US population. Higher rates of sexually transmitted infections were also observed at lower CD4 cell counts after adjusting for age. CONCLUSIONS AND RELEVANCE: Older PHIVY were at increased risk of viremia, immunosuppression, CDC-B events, CDC-C events, and mortality. Interventions to improve ARV therapy adherence and optimize models of care for PHIVY as they age are urgently needed to improve long-term outcomes among PHIVY.