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 less than or equal to 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.