Although type-specific IgG directed to the O-polysaccharide antigen of bacterial lipopolysaccharide (LPS) is protective in most models of LPS or bacterial challenge, no currently available IgG binds to LPS from all gram-negative bacteria. The ability of a peptide-IgG conjugate, CAP18(106-138)-IgG, to bind and neutralize LPS, to kill gram-negative bacteria, and to protect in a sensitized mouse model of LPS toxicity was studied. CAP18(106-138)-IgG bound LPS from multiple gram-negative bacteria in four different binding assays. In a fluid-phase RIA, half-maximal binding of 5 microg/mL 3H-labeled LPS occurred at 5-10 microg/mL CAP18(106-138)-IgG, similar to binding with monoclonal type-specific IgG. CAP18(106-138)-IgG neutralized LPS, as assessed by LPS-induced coagulation of limulus amebocyte lysate and production of tumor necrosis factor in vitro, was bactericidal for a wide range of gram-negative bacteria, and decreased LPS-induced lethality in sensitized mice. Antibacterial peptide-IgG conjugates merit further study as a novel adjunctive therapy for gram-negative sepsis.