OBJECTIVE: To estimate highly active antiretroviral therapy (HAART)-era incident rates for the first episode of noninfectious conditions in human immunodeficiency virus (HIV)-infected youth in order to identify HAART-era changes in the natural history of perinatal HIV infection. DESIGN: Multicenter prospective cohort study. SETTING: More than 80 sites in the United States including Puerto Rico. PATIENTS: Perinatally HIV-infected youth. MAIN OUTCOME MEASURES: Incidence rates (IRs) per 100 person-years were calculated for targeted noninfectious conditions occurring in perinatally HIV-infected children. A chi(2) test for linear trend was used to evaluate changes in the rates from 2001 to 2006. RESULTS: Two thousand five hundred seventy-five perinatally HIV-infected children (51%, female; 59%, black, non-Hispanic) were enrolled in Pediatric AIDS Clinical Trials Group (PACTG) 219C between 2000 and 2006 and were followed up for a median of 59 months. The 10 most common noninfectious conditions were pregnancy conditions (IR = 6.16; 95% confidence interval (CI), 3.9-9.3), birth defects (IR = 0.19; 95% CI, 0.1-0.3), gynecological dysplasias (IR = 5.92; 95% CI, 3.9-8.6), condyloma (IR = 0.15; 95% CI, 0.1-0.2), encephalopathy (IR = 0.38; 95% CI, 0.3-0.5), pancreatitis (IR = 0.30; 95% CI, 0.2-0.4), cardiac disorders (IR = 0.28; 95% CI, 0.2-0.4), renal disorders (IR = 0.26; 95% CI, 0.2-0.4), peripheral neuropathy (IR = 0.23; 95% CI, 0.2-0.4), and idiopathic thrombocytic purpura (IR = 0.15; 95% CI, 0.1-0.3). Among these conditions, 5 showed significant trends, with IRs increasing over time in pregnancy-related conditions (P < .001) and gynecological dysplasias (P = .02) while IRs decreased over time for encephalopathy (P < .001), pancreatitis (P = .002), and cardiac disorders (P = .007). CONCLUSIONS: Between 2001 and 2006, the incidence for 3 conditions decreased and increased for 2 others, demonstrating the change in medical issues and conditions in perinatally infected youth. Continued surveillance with appropriate tools will be needed to assess the long-term effects of HAART and HIV as well as development of new noninfectious conditions of HIV.