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We examined the epidemiology of invasive penicillin-resistant Streptococcus pneumoniae (PRSP) infections among residents of the Baltimore metropolitan area from 1995 through 1997. During this period, the proportion PRSP cases increased 42%, from 5.7% to 8.1% of cases. PRSP rates were highest among persons aged >5 and ≥65 years, black patients, and urban dwellers. However, the proportion of PRSP cases was higher among white persons (10%) than it was among black persons (5%) and among residents of suburban counties (10%) versus urban counties (6%). PRSP cases were more common in November-April (8%) than they were in May-October (5%), particularly for persons aged ≥65 years (10% vs. 1%). By use of logistic regression, white race, suburban residence, and winter respiratory season were found to be independent predictors of infection with PRSP. The incidence of PRSP is increasing in Baltimore, and the seasonality of PRSP suggests that recent antibiotic use, which is more common in winter months, may rapidly affect the prevalence of resistant pneumococcal infections.