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HIV-infected children are at increased risk of developing invasive Streptococcus pneumoniae disease.To determine the impact of the HIV epidemic on the epidemiology of invasive pneumococcal disease in hospitalized African children.Children <12 years of age with invasive pneumococcal disease were enrolled between March, 1997, and February, 1999.The seroprevalence of HIV was 64.9% (146 of 225). In children with pneumococcal isolates from serogroups 6, 9, 14, 19 or 23 (pediatric serogroups), pneumonia and pneumonia with concurrent meningitis was more common in HIV-infected children (P = 0.03 and P = 0.003, respectively), whereas septic shock occurred more often in HIV-uninfected children (P = 0.0003). The overall burden of severe invasive pneumococcal disease was 41.7 (95% confidence interval, 26.5 to 65.6) fold increased in HIV-infected compared with HIV-uninfected children. Reduced susceptibility to penicillin (45.9%vs. 27.9%, P = 0.009), trimethoprim-sulfamethoxazole (44.5%vs. 19.0%, P = 0.0002) and multiple drug resistance was more common in HIV-infected than in HIV-uninfected children (24.0%vs. 6.4%, P = 0.01), respectively. The increased burden of disease and reduced antibiotic susceptibility of pneumococcal isolates in HIV-infected children was because of a heightened susceptibility to disease caused by pediatric serogroups in these children than in HIV-uninfected children (P = 0.01). Although the case fatality rates did not differ between HIV-infected and -uninfected children, mortality in HIV-infected children with advanced AIDS (Stage C, 22 of 61; 36.1%) was greater than that in children with moderate AIDS (Stage B, 12 of 85; 14.1%, P = 0.002).In children with invasive pneumococcal disease caused by the pediatric serogroups, HIV-infected children have more antibiotic-resistant isolates and have a different clinical presentation than do HIV-uninfected children.