There are suggestions that the phylogeny of Streptococcus mutans, a member of the human indigenous biota that is transmitted mostly mother to child, might parallel the evolutionary history of its human host. The relatedness and phylogeny of plasmid-containing strains of S. mutans were examined based on chromosomal DNA fingerprints (CDF), a hypervariable region (HVR) of a 5.6-kb plasmid, the rRNA gene intergenic spacer region (IGSR), serotypes, and the genotypes of mutacin I and II. Plasmid-containing strains were studied because their genetic diversity was twice as great as that of plasmid-free strains. The CDF of S. mutans from unrelated human hosts were unique, except those from Caucasians, which were essentially identical. The evolutionary history of the IGSR, with or without the serotype and mutacin characters, clearly delineated an Asian clade. Also, a continuous association with mutacin II could be reconstructed through an evolutionary lineage with the IGSR, but not for serotype e. DNA sequences from the HVR of the plasmid produced a well-resolved phylogeny that differed from the chromosomal phylogeny, indicating that the horizontal transfer of the plasmid may have occurred multiple times. The plasmid phylogeny was more congruent with serotype e than with mutacin II evolution, suggesting a possible functional correlation. Thus, the history of this three-tiered relationship between human, bacterium, and plasmid supported both coevolution and independent evolution.The mutans streptococci (MS) are causally linked to dental caries in humans and in laboratory animals (22,44). Two members of the MS group, Streptococcus mutans and Streptococcus sobrinus, are associated with human caries, while the other members of the MS family are predominantly present in other mammals. This distribution of MS indicates host specialization. S. mutans is generally transmitted vertically, mother to child, and this mode of transmission results in the clustering of strains, not only within families (4,11,19,20), but within racial cohorts as well (8). This proclivity for vertical transmission along maternal lines could make the population structure of S. mutans relevant to the evolutionary history of its human host, not unlike the mitochrondrial-DNA model (6). At present, however, the population structure of S. mutans remains fragmented, and only hints of phylogenetically informative patterns in S. mutans populations exist (5,8,14,31).Genetic diversity is well documented within S. mutans. For example, variability among strains of S. mutans has been demonstrated for the presence of plasmids (8, 11, 23); mutacin I, II, III, and IV operons (5, 14, 33, 34, 46); serotype antigens (38, 46); competence (15,21,29); and the msm, bgl, cel, and gtfBC loci (46), among others. Indeed, the genome of S. mutans UA159 shows that nearly one-third of its open reading frames are of unknown function and 16% are unique to S. mutans. Recent work by Waterhouse and Russell (46) shows a mosaic of different genetic loci, or what they call "dispensable genes," ...