Rationale: There is conflicting evidence regarding sex differences in the outcome from severe sepsis and toxic shock. Superantigen-mediated toxic shock affects a higher proportion of female patients. Objectives: The objective of the current study was to investigate sexual dimorphism in superantigen-associated sepsis and in superantigen-mediated shock and to identify the key mechanisms responsible for this sex difference. Methods: We measured mortality and serum cytokines after induction of sepsis with isogenic superantigen-positive and -negative Streptococcus pyogenes in HLA class II transgenics. During superantigen-mediated toxic shock, we measured mortality, T cells responses, systemic TNF and TNF receptors, TNF-induced hepatocyte apoptosis, and conditioning of these responses by tamoxifen treatment. Main Results: In both superantigen-associated sepsis and in superantigen-mediated shock, serum TNF was increased in females compared with males. This was not attributable to a detectable difference in splenic TNF transcription, rather, serum soluble TNF receptors were higher in males. Pre-treatment of females with the estrogen receptor modulator, tamoxifen, increased serum soluble TNF receptors, reduced the early serum TNF response and improved mortality in females challenged with staphylococcal enterotoxin B. Lethal superantigen shock was characterized by hepatocyte apoptosis, and was reproduced by injection of TNF. Females had enhanced susceptibility to TNF-mediated lethality. TNF-induced hepatocyte apoptosis was greater in females, and was reduced by tamoxifen pretreatment. Conclusions: Sexual dimorphism in experimental superantigen toxic shock results from increased systemic TNF in females, coupled with an increased susceptibility to TNF-induced hepatocyte apoptosis. Both processes are abrogated by estrogen receptor modulators.