Naturally present antibacterial proteins play an important role in innate host defense. A synthetic peptide mimicking the C-terminal lipopolysaccharide (LPS)–binding domain of rabbit cathelicidin CAP18 was coupled to immunoglobulin (Ig) G to create CAP18106–138-IgG, a construct that, in concentrations equimolar to those of peptide alone, binds and neutralizes LPS and kills multiple gram-negative bacterial strains. The protective efficacy of CAP18106–138-IgG was evaluated in a model of cecal ligation and puncture in mice. A single intravenous administration of 20 mg/kg CAP18106–138-IgG protected against mortality, compared with sham-coupled IgG (P<.03). There was no protection offered by administration of equimolar peptide alone (P=.96). There was a trend toward protection in C3H/HeJ mice that are minimally sensitive to LPS (P=.06), suggesting that direct detoxification of LPS was not the only mechanism of protection. Chemical or genetic coupling of antimicrobial peptides to IgG may be a means of using these peptides to treat infections