Gram-negative bacterial sepsis continues to represent a significant cause of morbidity and mortality in hospitalized patients. Currently available medical therapy (antimicrobial agents, hemodynamic monitoring, aggressive fluid resuscitation, and nutritional support) for this disease process has reduced but not eliminated the severe consequences that may ensue. Recent investigations have demonstrated the ability of antibody directed against gram-negative bacterial lipopolysaccharide (LPS or endotoxin) to afford protection during experimental gram-negative bacillary sepsis. The core LPS-lipid A portion of endotoxin represents a determinant shared by many common gram-negative microorganisms that is luxuriantly expressed on the cell surface of rough mutants of Escherichia coli and Salmonella minnesota. These organisms or the outer membrane LPS isolated from them thus represent suitable immunogens for the development of cross-protective antibody preparations. Large quantities of highly cross-reactive antibody may potentially be obtained from several sources: murine or human monoclonal antibodies, immunization of large animals or humans with subsequent plasmapharesis and antibody isolation, affinity purification of large amounts of normal antibody, and pooling of prescreened lots of normal animal or human antibody that react to a particular bacterial antigen.