We conducted a retrospective study of all hospitalized human immunodeficiency virus (HIV)-infected patients from whom a strain of Streptococcus pneumoniae was isolated (n = 45) between January 1992 and September 1994, in order to determine the clinical manifestations and outcome of and risk factors for infection by S. pneumoniae with decreased susceptibility to penicillin G. Such strains were isolated from 14 patients (31%), of whom 8 had pneumonia, 2 had bronchial superinfection, 2 had sinusitis, and 2 were colonized. All infected patients made a clinical recovery regardless of the MIC of the isolate. Indexes of HIV disease stage (CD4+ cell count and p24 antigenemia), antiretroviral treatment, and hospital admission in the previous 3 months did not influence the susceptibility of the isolates. For HIV-infected patients, treatment with antibacterial agents—particularly trimethoprim-sulfamethoxazole—in the previous 3 months is associated with an increased risk for isolation of S. pneumoniae with decreased susceptibility to penicillin G (relative risk, 5.0; 95% confidence interval, 1.9–13.3).