Objective. —To estimate drug susceptibility patterns of Streptococcus pneumoniae in selected hospitals in the United States and to characterize the epidemiology of invasive drug-resistant pneumococcal infections. Design. —Minimum inhibitory concentrations (MICs) for a variety of commonly used antimicrobial drugs were determined for pneumococcal isolates submitted to the Centers for Disease Control and Prevention (CDC). Risk factors for drug-resistant pneumococcal infection were evaluated. Setting. —Hospital laboratories in the United States submitting pneumococcal isolates to the CDC between October 1, 1991, and September 30, 1992. Participants. —A total of 544 persons with pneumococci isolated from normally sterile sites. Results. —A total of 13 hospitals in 12 states actively participated in an ongoing pneumococcal surveillance study. Resistance to penicillin was detected in 6.6% of isolates, including 1.3% of isolates with MICs of 2.0 μg/mL or more (compared with Conclusions. —Emergence of drug-resistant pneumococcal infections will present critical challenges to clinicians for treating patients with pneumococcal disease. Widened and intensified surveillance is needed. These data suggest that current recommendations for use of 23-valent pneumococcal capsular polysaccharide vaccines should be aggressively promoted and that development and evaluation of new conjugate pneumococcal vaccines may be a crucial part of strategies for prevention. (JAMA. 1994;271:1831-1835)