Pharyngeal colonization by Streptococcus pneumoniae was evaluated in 103 human immunodeficiency virus (HIV)-infected subjects (<200 CD4 cells/microL, 57; > or = 200 CD4 cells/microL, 46) and 39 non-HIV-infected controls who were participants in a vaccine study. At baseline, 7%, 20%, and 10% of subjects in the <200 and > or = 200 CD4 cell groups and in the control group were colonized with S. pneumoniae: Rates at 6 months were 23%, 22%, and 0%, respectively. Of 34 isolates from HIV-infected subjects, 25 were penicillin-resistant and 19 were resistant to > or = 3 antimicrobials; of 8 isolates from controls, 1 was resistant. Resistance to trimethoprim-sulfamethoxazole was significantly higher among HIV-infected subjects with <200 CD4 cells/microL than in those with more CD4 cells. Polymerase chain reaction DNA analysis with BOX primers demonstrated that 12 HIV-infected subjects were persistently colonized with the same S. pneumoniae strain for > or = 1 month compared with none of the controls. HIV-infected subjects were more likely to be persistent pneumococcal carriers and to carry antibiotic-resistant isolates than were non-HIV-infected subjects.