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Positive pneumococcal cultures of specimens from adult inpatients at San Francisco General Hospital (SFGH) during the period of 11 August 1994 through 31 December 1996 were identified retrospectively. Of the isolates recovered, 15.5% were not penicillin-susceptible (MIC, ≥.1 μg/mL). A case-control study was performed to evaluate risk factors for colonization or infection with penicillin-nonsusceptible Streptococcus pneumoniae (PNSP) and outcomes. Cases (n = 65) were adult inpatients with a positive culture for PNSP, and controls (n = 411) were adult inpatients with a positive culture for penicillin-susceptible pneumococci (PSSP) and no evidence of PNSP. Cases were less likely to have pneumococcal bacteremia (15.4% versus 39.4%; P < .001) and less likely to have pneumonia (50.8% versus 68.9%; P = .006). In a multiple logistic regression model, recent hospital admission and absence of bacteremia were independent predictors of penicillinnonsusceptibility. Human immunodeficiency virus infection, mortality, and length of hospitalization were not significantly different among cases and controls. These data suggest that PNSP may be less virulent (cause less pulmonary infection) and/or less invasive (cause fewer bloodstream infections) than PSSP at SFGH.