We performed a 3-year retrospective study of Streptococcus pneumoniae blood culture isolates recovered at Baragwanath Hospital, Soweto, South Africa, from 1993 to 1995. The study group comprised 457 patients, including 98 children, of known human immunodeficiency virus (HIV) serostatus. Of these patients, 70 (30 [8.4%] of 359 adults and 40 [40.8%] of the 98 children) were infected with penicillin-resistant S. pneumoniae strains (minimal inhibitory concentration, > or = 0.12 microg/mL); 56 of these strains were intermediately resistant to penicillin. HIV-positive patients had significantly more penicillin-resistant isolates than did HIV-negative patients (43 [29.7%] of 145 HIV-positive patients vs. 27 [8.6%] of 312 HIV-negative patients; P < .001); this difference was found for both adults (19% vs. 4.3%; P < .001) and children (53.3% vs. 30.2%; P < .0343). Multiple resistance occurred more frequently in HIV-positive children (P = .02). HIV-positive adults had a statistically significant increase in the percentage of serogroups and serotype usually found in children and commonly associated with antimicrobial resistance, i.e., serotype 14 and serogroups 6, 19, and 23 (48% vs. 28.6%; P < .001). The increased prevalence of serogroups or serotypes usually found in children was also found among penicillin-susceptible strains. These data suggest that HIV-infected adults may again become susceptible to the serogroups or serotypes found in children.