The role of anti-endotoxin antibodies in the management of gram-negative bacteremia and the experimental and clinical studies on the cross-protection afforded by core LPS antibodies are reviewed. These studies did not achieve clarification of the epitope(s) and effector mechanism(s) involved in protection. Recently, two anti-lipid A IgM monoclonal antibodies, designated E5 and HA-1A, have been investigated in patients with gram-negative bacterial infections and clinical manifestations of septicemia. E5 reduced the mortality of patients if they were not in shock, whether they were bacteremic or not. A confirmatory study has been initiated. In contrast to E5, HA-1A protected patients whether they were in shock or not, but only when they were bacteremic at randomization. Although these studies suggest beneficial effects, the type of patients who may benefit from this expensive therapy should be further defined. Further investigations are needed to clarify the mechanisms of protection of these antibodies.