Cytokines elicited by superantigens have been suggested to play a central role in severe systemic clinical manifestations of gram‐positive sepsis. Here we provide evidence for a potent inflammatory cytokine response in acute invasive group A streptococcal infections, and show a direct correlation between the magnitude of this response and the severity of systemic manifestations of the disease. Severe invasive cases suffering from toxic shock and/or necrotizing fasciitis had significantly higher frequencies of IL‐2‐, IL‐6‐, and TNF‐α‐producing cells in their circulation as compared to non‐severe invasive cases (p=0.05–0.01). This difference was even more accentuated when severe and non‐severe cases infected with a clonal M1T1 strain were compared (p=0.03–0.004). To determine whether host factors were responsible for this difference in magnitude of cytokine responses, paired age‐ and gender‐matched severe and non‐severe M1T1 cases (n=8) were tested in vitro during their convalescent phase for immune response to superantigens produced by their infecting isolate. The results showed persistent and inherent differences in the magnitude of proliferative and cytokine responses of severe and non‐severe patients to the streptococcal superantigens to which they had been exposed during infection. Thus, the study provides evidence that patients with a propensity to produce higher levels of inflammatory cytokines in response to streptococcal superantigens develop significantly more severe systemic manifestations than patients who have a propensity to produce lower levels of inflammatory cytokines to the same superantigens. We therefore conclude that host factors influence the magnitude of cytokine responses to superantigens and consequently the clinical outcome of the infection.