A mutant of Streptococcus mutans 6715 wild type (WT), designated C4, has been shown previously to be defective in glucosyltransferase synthesis of insoluble glucan and to have low virulence in monoassociated gnotobiotic rats. The present investigation was concerned with the detection of WT-like variants of C4 in monoassociated rats, the supplantation of C4 by these WT-like organisms, and finally, the pathogenic potential of these WT-like organisms in gnotobiotic rats. In the first series of longitudinal studies with C4-monoassociated rats, WT-like organisms were detected at a low frequency (0.001%) in oral swab samples only one of four cages of animals analyzed on day 7 after infection (age 27 days). The frequency of variants isolated from animals in the one cage increased, and by age 45 days these organisms represented approximately 1% of the mandibular plaque flora. After random redistribution of rats in the four cages (age 45 days), microbial analysis of oral swab samples (age 60 days) demonstrated the presence of variants in samples taken from rats in all four cages. The frequency of recoverable variants increased in older animals (age 90 days) and correlated with high caries activity. WT-like organisms were transmissible, since offspring (age 45 days) from these animals had high levels of variants as well as high caries activity. Similar results were obtained in a second longitudinal study; however, variants, although present in all four cages, were not detected until rats were 45 days old. All variant isolates exhibited morphological, biochemical, and in vivo virulence characteristics more similar to S. mutans 6715 WT than to C4. In vitro mixing experiments with C4 and either WT or a selected variant suggested that C4 was rapidly displaced by WT organisms. The results of this investigation demonstrate that the glucosyltransferase-defective, low-virulence C4 reverts to virulent WT-like organisms in vivo which compete more favorably for smooth surfaces than C4. Subsequently, these variants reached significant numbers in plaque which correlated with increased dental caries.