To improve the management of lower respiratory tract infections (LRTI) in human immunodeficiency virus type 1 (HIV-1)-infected children, we assessed the burden of disease, clinical outcome and antibiotic susceptibility of bacteria causing severe community-acquired LRTI in children. A prospective, descriptive study was performed in the pediatric wards at a secondary and tertiary care hospital in South Africa. Urban black children aged 2-60 months admitted with severe acute LRTI from March 1997 through February 1998 were enrolled. HIV-1 infection was present in 45.1% of 1215 cases of severe LRTI. Bacteremia occurred in 14.9% of HIV-1-infected and in 6.5% of HIV-1-uninfected children (P<.00001). The estimated relative incidence of bacteremic severe LRTI in children aged from 2 to 24 months were greater in HIV-1-infected than in -uninfected children for Streptococcus pneumoniae (risk ratio [RR], 42.9; 95% confidence interval [CI], 20.7-90.2), Haemophilus influenzae type b (RR, 21.4; 95% CI, 9.4-48.4), Staphylococcus aureus (RR, 97.9; 95% CI, 11.4-838.2) and Escherichia coli (RR, 49.0; 95% CI, 15.4-156). Isolation of Mycobacterium tuberculosis was also more common in HIV-1-infected than in -uninfected children (RR, 22.5; 95% CI, 13.4-37.6). In HIV-1-infected children, 60% of S. aureus and 85.7% of E. coli isolates were resistant to methicillin and trimethoprim-sulfamethoxazole, respectively. The case-fatality rates among HIV-1-infected children was 13.1%, and among HIV-1-uninfected children, 2.1% (adjusted odds ratio [AOR]; 6.52, 95% CI, 3.53-12.05; P<.00001). The changing spectrum of bacteria and antibiotic susceptibility patterns in HIV-1-infected children requires a reevaluation of the empirical treatment of community-acquired severe LRTI in children from developing countries with a high prevalence of childhood HIV-1 infection.