We performed a prospective study of all infections with Streptococcus pneumoniae documented during a 22-month period at our hospital. A total of 163 clinically significant strains of S. pneumoniae were isolated from 139 patients whose ages ranged from 8 days to 91 years (mean ± SD, 42.6 years ± 26.8 years). Twenty percent of the patients had cancer, and 18% were infected with the human immunodeficiency virus. Pneumococcal infection was nosocomially acquired in one-fourth of cases. One-third of patients had nonpneumonic disease. A wide range of serotypes were isolated, and 42.5% of all strains were nonsusceptible—i.e., showed either intermediate or high-level resistance—to penicillin. The rates of resistance to chloramphenicol, erythromycin, and tetracycline were 23%, 10.8%, and 48.2%, respectively. Twenty-two percent of the infected patients died, with a 15.8% mortality directly attributable to pneumococcal infection. Factors associated with infection by strains of S. pneumoniae not susceptible to penicillin included an age of ⩽10 years, immunosuppression, the presence of a rapidly fatal underlying disease, previous antimicrobial therapy, and infection by serotypes 14 and 23. All clinically significant isolates of S. pneumoniae should be submitted for antimicrobial susceptibility studies, and, whenever a high prevalence of resistance to penicillin and macrolides is detected, the use of these well-established empirical therapeutic regimens should be reconsidered.