Treatment of infections with drug-resistant strains of Streptococcus pneumoniae (pneumococcus) may fail; whether drug resistance is associated with an increase in the number of serious infections in the community is unknown. We evaluated the relationship between the proportion of antimicrobial-resistant S. pneumoniae isolates and the number of cases of invasive pneumococcal disease. Linear regression models included 1996 county-level data from 38 counties participating in the US Centers for Disease Control and Prevention's Active Bacterial Core Surveillance. Separate models evaluated hospitalized children aged <5 years, nonhospitalized children aged <5 years, adults aged 18-64 years, and adults aged >64 years. The proportion of isolates resistant to > or =3 drug classes was associated with invasive disease in both hospitalized (P=.06) and nonhospitalized (P=.001) children. The proportion of multidrug-resistant pneumococcal isolates did not predict invasive cases among adults. The increasing prevalence of multidrug-resistant pneumococci among children may be leading to an increase in invasive disease.