We performed a comprehensive analysis of the molecular, serological, and clinical features of 16 consecutive cases of invasive streptococcal disease (ISD). The majority of cases were linked to two group A streptococcus (GAS) clones closely related by pulsed-field gel electrophoresis (PFGE) and designated as PFGE-1 and PFGE-1.1. These clones, serotyped as M-3, T-3/B3264, carried an allelic variant of the gene that encodes pyrogenic exotoxin A (speA3) and the gene that encodes streptococcal superantigen (SSA) but different emm alleles that encode M-protein. The characteristics and clinical features of patients were similar to those described in previous reports, regardless of the responsible GAS clone. However, worse clinical outcomes (shock and death) were more frequent when patients infected with PFGE1/1.1 clones were considered as a group and compared with all other patients as a group. One striking feature in some patients with deep tissue infection was a lack of inflammatory cells despite the presence of numerous streptococci. An evaluation of PFGE profiles of GAS isolated elsewhere demonstrated that the PFGE-1 clone has caused invasive disease in other locations in the United States and in Japan.