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(See the Editorial Commentary by Huttner and Samore, on pages 640–643.)Background.Streptococcus pneumoniae infections have become increasingly complicated and costly to treat with the spread of antibiotic resistance. We evaluated the relationship between antibiotic prescribing and nonsusceptibility among invasive pneumococcal disease (IPD) isolates.Methods. Outpatient antibiotic prescription data for penicillins, cephalosporins, macrolides, and trimethoprim-sulfamethoxazole were abstracted from the IMS Health Xponent database to calculate the annual number of prescriptions per capita. We analyzed IPD data from 7 of the Centers for Disease Control and Prevention’s Active Bacterial Core surveillance sites (population, 18.6 million) for which data were available for the entire time period under study (1996–2003). Logistic regression models were used to assess whether sites with high antibiotic prescribing rates had a high proportion of nonsusceptible and serotype 19A IPD.Results. Yearly prescribing rates during the period 1996–2003 for children <5 years of age decreased by 37%, from 4.23 to 2.68 prescriptions per capita per year (P < .001), and those for persons ≥5 years of age decreased by 42%, from 0.98 to 0.57 prescriptions per capita per year (P < .001); increases in azithromycin prescribing were noted for both groups. Sites with high rates of antibiotic prescribing had a higher proportion of IPD nonsusceptibility than did low-prescribing sites (P = .003 for penicillin, P < .001 for every other antibiotic class). Cephalosporin and macrolide prescribing were associated with penicillin and multidrug nonsusceptibility and serotype 19A IPD (P < .001).Conclusions. In sites where antibiotic prescribing is high, the proportion of nonsusceptible IPD is also high, suggesting that local prescribing practices contribute to local resistance patterns. Cephalosporins and macrolides seem to be selecting for penicillin- and multidrug-resistant pneumococci, as well as serotype 19A IPD. Antibiotic use is a major factor contributing to the spread of antibiotic resistance; strategies to reduce antibiotic resistance should continue to include judicious use of antibiotics.