Previous antibiotic exposure is one of the most important predictors for acquisition of penicillin-nonsusceptible Streptococcus pneumoniae (PNSP) infection. To determine the impact of duration of exposure to different antibiotic classes, a study of 303 patients with S. pneumoniae bacteremia was undertaken. Ninety-eight cases of bacteremia (32%) were caused by a penicillin-nonsusceptible isolate. Bivariate analysis revealed that use of beta-lactams, sulfonamides, and macrolides within the last 1 and 6 months before presentation was associated with PNSP bacteremia (P<.05). Fluoroquinolone consumption was not related to bacteremia due to PNSP (P>.1). Both short- and long-term beta-lactam use significantly increased the risk for PNSP infection. Logistic regression analysis revealed that use of beta-lactams and macrolides in the 6 months before the first positive blood culture result were independent risk factors (P<.05). Risk for acquiring PNSP infection depends on both the class of antibiotic to which the patient was exposed and the duration of therapy.