The toxicity of toxic shock syndrome (TSS) toxin-1 (TSST-1) was evaluated in female, specific pathogen-free rabbits and conventional rabbits. Results after intravenous injections of TSST-1 given to both types of rabbits indicated that specific pathogen-free rabbits were resistant to the lethal effects observed in conventional rabbits. Lethality could be prevented by simultaneous administration of polymyxin B, and analysis of serum before and after dosing confirmed that dosing with TSST-1 resulted in circulating endotoxin. Analysis of sera from humans with TSS showed that endotoxin was present in acute-phase sera but not in convalescent-phase sera. These observations suggest that endogenous endotoxin contributes to rabbit susceptibility to TSST-1 and may play a role in human TSS.