The heptavalent pneumococcal conjugate vaccine (PCV7) has decreased the incidence of pediatric invasive pneumococcal disease (IPD) in the United States. Few data exist on the changing IPD incidence in HIV-infected children. Diagnostic codes and clinical microbiology laboratory records identified cases of IPD from 1989 to 2006 in perinatally-infected children <18 years of age followed at an urban HIV clinic. IPD incidence was calculated and serotype distribution and antibiotic resistance were recorded. Two-hundred fifty-six patients were followed for 1756 person-years (PY). The sample was 59% female, 76% black, 14% white, and 8% Hispanic. Of 21 episodes of IPD (1200/100,000 PY), 17 (81%) were female. IPD cases had a median age of 6.3 years (interquartile range [IQR]: 2.3-9.9 years), median CD4% of 17% (IQR: 11-28%), and median CD4 count of 415 cells/mm (range, 2-1699 cells/mm). Bacteremia was the commonest form of IPD (19 episodes; 1080/100,000 PY). After HAART introduction in 1996, the incidence of IPD decreased 84% from 1862/100,000 PY in 1989-1995 to 292/100,000 PY in 1997-1999 (incidence rate ratio [IRR]: 0.16, P = 0.03). After PCV7 introduction in 2000, IPD incidence showed a nonsignificant increase from 292 of 100,000 PY in 1997-1999 to 860 of 100,000 PY in 2001-2006 (IRR: 2.94; P = 0.16). The percentages of IPD isolates nonsusceptible to penicillin and trimethoprim-sulfamethoxazole were 19% and 33%, respectively. Vaccine serotypes accounted for 38% of isolates, vaccine-related 14%, nonvaccine 33%, and the serotype was unknown in 14%. The incidence of IPD among perinatally HIV-infected children decreased after the introduction of HAART. Ongoing monitoring is required to determine the effect of PCV7 on IPD in this vulnerable population.