We assessed the distribution of the clonal groups (as determined by pulsed-field gel electrophoresis) of penicillin-nonsusceptible Streptococcus pneumoniae that caused invasive pneumococcal infection in the Baltimore metropolitan area during 1995 and 1996. Although S. pneumoniae caused invasive disease in individuals from a variety of demographic groups and locations, strains isolated during the season in which respiratory infections are most common were more likely to be from clonal groups associated with penicillin resistance than from other groups.