Staphylococcal pyrogenic exotoxin (PE) ty pe C enhanced the susceptibility of rabbits to lethal shock by endotoxin by as much as 50,000-fold. A graph of log PE type C dose used for pretreatment versus log 50% lethal dose of endotoxin gave a straight line with a slope of approximately -1. Rabbits that received PE type C alone showed fevers only, but those given both PE ty pe C and endotoxin showed initial fever followed by hypothermia, labored breathing, diarrhea, evidence of vascular collapse, and finally death. When a PE type C dose of 3 micrograms/kg was used, pretreatment of the animals with PE for 2 h before giving the endotoxin was required to obtain maximal susceptibility. However, when 15 micrograms of PE type C per kg was utilized, the endotoxin could be given before, concurrently, or after PE type C. The capacity of PE type C to prepare rabbits for enhanced susceptibility to endotoxin was lost after 24 to 48 h. Animals could be protected from enhanced susceptibility to endotoxin by prior immunization with either PE type C or endotoxin. However, 30% of the rabbits which were immunized with PE type C failed to develop immunity, and after three injections of PE type C, these animals developed gram-negative bacteremia and succumbed. In addition, rabbits with diarrhea initially, possibly caused by Pasteurella infection, died less than 24 h after a single injection of PE type C.