As part of a nationwide surveillance in The Netherlands during 1994–1997, 53 patients with invasive group A streptococcal (GAS) infections were evaluated for medical history, symptoms, and outcome. Patients' isolates were tested for the production of pyrogenic exotoxins A (SPE-A) and B (SPE-B). Acute-phase sera from all patients and convalescent sera from 12 patients were investigated for the presence of antibodies against SPE-A and SPE-B. Twenty-three patients developed toxic shock-like syndrome and 16 died. Absence of antibodies against SPE-A and/or SPE-B was a risk factor for developing invasive streptococcal disease. Toxic shock and mortality were associated with a lack of anti-SPE-A antibodies ( P < .025). Anti-SPE-A antibodies were found in convalescent sera from all patients infected by speA- positive isolates. Virtually all invasive speA -positive streptococci expressed SPE-A protein in vitro. Thus antibodies against SPE-A appeared vital for mediating the outcome of invasive GAS disease in this population.