Rabbit antiserum against the endotoxins in smooth and rough bacteria, as well as rabbit antiserum against the endotoxins in heterologous organisms, prevented death in mice given lethal intravenous doses of endotoxin. These results indicated that different Gram-negative bacterial species share a protective antigen unrelated to “O” antigen. Similar protection was then attempted in mice with antisera prepared in the same animal family, i.e., rats. Instead of protecting, such sera sensitized mice so that otherwise sublethal doses of intravenous homologous endotoxin produced deaths from anaphylaxis within 1 hr. These small doses of endotoxin did not produce anaphylactic deaths in mice given immune rat serum prepared against unrelated (heterologous) endotoxins. The differential effects of protective rabbit antibody and anaphylactic rat antibody are thus attributed to reactions with different antigenic sites on the endotoxin molecule: anaphylactic antibody with the oligosaccharide “O” determinants, and protective antibody with a core antigen. Solution of the anaphylaxis problem is essential to the development of protective antisera against lethal endotoxemia.