A nationwide retrospective study was performed in France to describe the susceptibility of Streptococcus pneumoniae strains to penicillin G and to identify risk factors for infection with nonsusceptible strains. From January 1991 to May 1992, 10,350 S. pneumoniae strains were recorded. The overall rate of penicillin-nonsusceptible pneumococcal (PNSP) strains was 11%; specific prevalence rates, according to the sources of the isolates, were as follows: blood, 6%; cerebrospinal fluid, 10%; lower respiratory tract, 10%; and middle ear, 18%. Large variations in regional distribution were observed. In 85% of cases, PNSP strains belonged to serogroup 23, 19, 6, 14, or 9, by order of decreasing frequency. A logistic regression model identified the following factors as being associated with PNSP infections: age of < 15 years (OR = 2.01), isolation of the organisms from the upper respiratory tract (OR = 2.36) or from sinus and middle ear (OR = 1.63), HIV infection (OR = 2.01), beta-lactam antimicrobial therapy in the previous 6 months (OR = 1.99), and nosocomial acquisition (OR = 2.12). The attributable risk of beta-lactam antimicrobial therapy in the previous 6 months was 19%, showing that suppression of this factor alone could not eradicate PNSP infections.