To determine if recent cases of invasive group A streptococcal disease were caused by strains with a unique characteristic, 117 isolates Streptococcus pyogenes from patients with a variety of diseases, including necrotizing fasciitis and toxic shock syndrome, were analyzed. Significant genomic heterogeneity was observed among selected isolates, as determined using pulsed-field gel electrophoresis. The frequency of the bacteriophage-associated streptococcal erythrogenic toxin genes A and C (speA and speC) among the isolates was 44% (49/112) and 34% (38/112), respectively. Forty-three percent of speA-positive isolates produced streptococcal erythrogenic toxin (SPE) A in vitro. Seventy-six percent (85/112) of isolates produced SPE B in vitro, and in contrast to SPE A, little variation in the concentration of SPE B in broth culture supernatants was detected. The genetic and phenotypic heterogeneity observed among isolates from recent cases of severe infection does not support a clonal basis for the resurgence of invasive streptococcal infections.