The experimental and clinical studies underlying the concept of cross-protection afforded by core lipopolysaccharides (LPS) antibodies are reviewed. These studies did not allow to clarify the epitope(s) and the effector mechanism(s) involved in the protection. Recently, two antilipid A IgM monoclonal antibodies, called E5 and HA-1A, have been investigated in patients with Gram-negative infections and a clinical picture of septicemia. E5 reduced the mortality of patients, bacteremic or not, but only as long as they were not in shock. A confirmatory study has been initiated. In contrast to E5, HA-1A protected patients in shock, but only when they were bacteremic at randomization. However, experimental studies have yielded contradictory results concerning the protective power of this antibody. Although the clinical studies suggest a beneficial effect of both antibodies in some patients, no definitive conclusions can be drawn until the extensive data will be published, and until further experimental investigations will have clarified the protective power of these antibodies.