Isolates of Streptococcus pneumoniae from 103 patients were submitted for serotyping and determination of the minimum inhibitory concentration (MIC) for penicillin. Isolates from 16 patients were relatively resistant to penicillin (MIC, 0.1 to 0.5 micrograms/mL). In a study to determine if the patients with relatively resistant pneumococci (RRP) differed from patients with normally susceptible pneumococci, 18 patients with RRP showed no significant difference from their matched controls in antibiotic use during the two months prior to isolation of the pneumococcus. Other variables that showed no significant difference between the two groups were (1) antibiotic use in household contacts in the previous six months, (2) presence of chronic infection in the case or control patients, and (3) recurrence of pneumococcal infection following therapy. The high rate of relative resistance to penicillin is heretofore unknown in a general, unconfined population in this country. The case-control study suggests that no strong relationship exists between isolating RRP and prior penicillin administration. More extensive surveys in the United States are needed.