The role of streptococcal pyrogenic exotoxin A (SPEA) was evaluated in a murine model of fasciitis and multiorgan failure due to a toxigenic strain of Streptococcus pyogenes. Increased serum levels of SPEA at 15 and 21 h were associated with a survival time of <24 h. Levels of SPEA correlated with interleukin-6 levels. Immunostaining showed SPEA localized to renal and hepatic cells. Neutralizing rabbit antibody to SPEA was administered to mice challenged with S. pyogenes, but no effect on survival was observed. Vaccination of mice with recombinant SPEA enhanced mortality due to streptococcal infection, despite the development of neutralizing immunity to the toxin prior to infection. Hence, SPEA is produced systemically during S. pyogenes soft-tissue infection, and increased levels are associated with reduced survival. In this model, however, SPEA did not appear to play a dominant role in pathogenesis; passive immunization against SPEA was not protective, and active immunization enhanced mortality.