During a 12-month period we tested all isolates ofStreptococcus pneumoniaerecovered from patients at St. Louis Children's Hospital for resistance to penicillin and other antibiotics. Twenty-seven (20%) of 136 had relative penicillin resistance (minimum inhibitory concentration 0.1 to 1.0 μg/ml) and 8 (6%) were fully resistant (minimum inhibitory concentration ≥ 2.0 μg/ml). Sixteen percent from blood and cerebrospinal fluid were resistant, compared with 30% from other body sites. The resistant isolates were of diverse serotypes and included 38% intermediate and 6% resistant to cefotaxime, 40% resistant to trimethoprim-sulfamethoxazole and 20% resistant to erythromycin. Patients with resistant isolates were more likely to have taken antibiotics of the aminopenicillin class and to be of the white race. We conclude that penicillin-resistant pneumococci, including some with resistance to third generation cephalosporins and some with multidrug resistance to non-beta-lactam antibiotics, are widespread in the St. Louis area. The presence of these stains requires reconsideration of current approaches to the antibiotic therapy of a variety of infectious diseases in which pneumococci play a prominent role.