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Objective. To determine whether there are any risk factors that differentiate children with systemic infections due to Streptococcus pneumoniae relatively or fully resistant (minimum inhibitory concentration >0.1 micrograms/mL) to penicillin from those children with infections due to S pneumoniae susceptible to penicillin.Retrospective case-control study.A large children's hospital.Forty-three children with systemic penicillin-resistant S pneumoniae infections identified at Texas Children's Hospital over the 51-month period from January 1989 through March 1993. Each case had one or two controls matched only for age and date of S. pneumoniae infection. Sixty-six controls were selected from a group of 341 children with susceptible isolates.Variables compared included gender, race, diagnosis, underlying conditions, past hospitalization, geographic area of residence, antibiotic use in past month, amoxicillin-clavulanic acid use in past month, and outcome.Thirty-seven patients (86%) had relatively resistant isolates (minimum inhibitory concentration range 0.125 to 1.0 micrograms/mL) and six patients (15%) had fully resistant isolates (minimum inhibitory concentration range 2.0 to 8.0 micrograms/mL). Thirty-three percent of the cases vs 36% of the controls had underlying conditions. Seventy-one percent of the cases vs 39% of the controls had received antibiotics in the previous month. Compared with their matched controls, the patients with penicillin-resistant systemic pneumococcal infections were more likely (P = .02) to have received a course of antibiotics within the month prior to their infection.The only identified associated risk factor in children who developed a systemic penicillin-resistant pneumococcal infection appears to have been the use of antibiotics within the month prior to their infection. Pediatrics 1993;92:761-767; penicillin, Streptococcus pneumoniae.