In an effort to understand the molecular genetic basis of temporal variation in frequency and severity of bacterial disease, genetic relationships among strains of Streptococcus pyogenes that caused scarlet fever epidemics in Canada in the early 1940s and in eastern Germany in the 1960s to 1980s were studied. Application of multilocus enzyme electrophoresis and comparative sequencing of the gene (speA) encoding streptococcal pyrogenic exotoxin A (scarlet fever toxin) revealed that new waves of scarlet fever are associated with an increase in frequency of S. pyogenes clones carrying variant speA alleles. This finding suggests that the occurrence of new scarlet fever epidemics can be predicted by comprehensive monitoring of the frequency of S. pyogenes clones with variant toxin alleles.