As part of ongoing national surveillance, serotyping and antimicrobial susceptibility testing were done on all pneumococcal isolates recovered from normally sterile body sites of patients at 12 hospitals in 11 states during 1993-1994. Of 740 isolates, 14.1% were penicillin-nonsusceptible Streptococcus pneumoniae (PNSP; MIC > or = 0.1 microgram/mL), 3.2% were penicillin-resistant (MIC > or = 2.0 micrograms/mL), and 25.5% were nonsusceptible to more than one antimicrobial agent. PNSP were more prevalent among children < 6 years old (18.4%) than patients > or = 18 years old (11.7%) and among white persons (16.2%) than black persons (12.1%). PNSP represented 15 serotypes, but 89% of PNSP were serotypes in the 23-valent pneumococcal vaccine. The proportion of isolates with reduced susceptibility and the number of serotypes of nonsusceptible strains are increasing in the United States. Improved local surveillance for PNSP infections, judicious use of antibiotics, and development and use of effective pneumococcal vaccines will be required to treat and prevent disease caused by these strains.