A collection of 2,209 isolates of six polysaccharide capsule types of Haemophilus influenzae, including 1,975 serotype b isolates recovered in 30 countries was characterized for electrophoretically demonstrable allele profiles at 17 metabolic enzyme loci. Two hundred eighty distinct multilocus genotypes were distinguished, and cluster analysis revealed two primary phylogenetic divisions. The population structure of encapsulated H. influenzae is clonal. Currently, most of the invasive disease worldwide is caused by serotype b strains of nine clones. Strains producing serotype c, e, and f capsules belong to single divisions and have no close genetic relationships to strains of other serotypes. Serotype a and b strains occur in both primary phylogenetic divisions, probably as a result of transfer and recombination of serotype-specific sequences of the cap region between clonal lineages. A close genetic relatedness between serotype d isolates and some strains of serotypes a and b was identified. There are strong patterns of geographic variation, on an intercontinental scale, in both the extent of genetic diversity and the clonal composition of populations of encapsulated strains. The analysis suggests that the present distribution of clones is, in part, related to patterns of racial or ethnic differentiation and historical demographic movements of the human host populations.