To determine whether nasopharyngeal carriage isolates of Streptococcus pneumoniae are of the same genetic background as isolates that caused invasive disease in one community, IS1167 and box A genotypes were obtained for 182 pneumococcal isolates from children living in central Tennessee. The isolates represented 70 combined IS1167-boxA genotypes. The genotypic diversity of the invasive isolates was significantly less than that of the total population (P = .003). Most of the carriage isolates belonged to genotypes unique to carriage, whereas most of the invasive isolates belonged to genotypes common to carriage and disease (P = .02). Monte Carlo simulations showed a greater number of genotypes unique to carriage than can be explained by chance (P < .05 in all cases). Two genotypes were identified by multilocus sequence typing as members of globally disseminated clones, and one such genotype that was strictly carriage in this sample caused disease in other studies. Thus, clones can have different propensities for carriage and invasion.