Immune-defective and immunologically normal F1 mice derived from the CBA/N strain were used to study the influence of anti-endotoxin antibody on the lethal effects of endotoxin. Immune-defective F1 male mice were unable to make specific responses to purified preparations of E. coli O111:B4 endotoxin, whereas their immunologically normal F1 female littermates made excellent responses. The ability to form antibody to lipopolysaccharide (LPS) in these F1 mice did not influence either their natural resistance to endotoxin challenge or the effects of pretreatment with sublethal amounts of endotoxin on subsequent challenge with higher normally lethal doses. Furthermore, transfer of sera with high titers of anti-LPS antibody to mice prior to challenge with LPS failed to protect. Thus, anti-LPS antibody does not appear to play a critical role in protection of immune-defective (CBA/N X DBA/2) F1 male mice to the lethal effects of endotoxin or to the protective effects of a single sublethal dose of endotoxin on subsequent endotoxin challenge.