The protection by antisera to O antigens and antigens (lipid A, the Re 595 mutant of Salmonella minnesota, and the J5 mutant of Escherichia coli) of the core portion of endotoxin against lethal challenge with lipopolysaccharide (LPS) was compared. Rabbits immunized with the Re mutant developed antibody that protected mice against challenge with S. minnesota or Salmonella typhosa LPS. Antisera to heterologous O antigen and lipid A were not protective, whereas homologous antisera and antiserum to the Re or J5 mutant protected against lethal challenge. On a volumetric basis, O-specific antiserum was consistently somewhat more protective than antiserum to the Re mutant, which was slightly more protective than antiserum to the J5 mutant. When comparisons were made using passive transfer to similar quantities of hemagglutinating or precipitating antibody, antiserum to the Re mutant was considerably more protective than O-specific antiserum. This greater protection is hypothesized to result from more effective masking of the toxic lipid A moiety by antibody to the rough mutants than by O-specific antibody.