Cathelicidins are a family of antibacterial peptides. Human cathelicidin LL-37 inhibits the binding of endotoxin lipopolysaccharide (LPS) to CD14-positive cells and could ameliorate sepsis. The aim of this study was to observe the effect of LL-37 on sepsis in neonatal rats. Intraperitoneal injection (IPI) of LPS was used to create sepsis in suckling rats. Group 1 rats were given LPS with LL-37, group 2 rats were given LL-37 2 h after LPS, and group 3 rats were given LPS without LL-37. Control group rats were given isovolemic normal saline by IPI. Rats given LL-37 IPI were divided into seven subgroups. Following IPI, an overall assessment score (OAS) and rectal temperature (RT) were assessed hourly. Serum C-reactive protein (CRP) was also assessed at death or at sacrifice 10 h after IPI. All rats in group 3 died. For rats receiving lower doses of LL-37 in groups 1 and 2, mortality was decreased. No deaths occurred among those receiving higher doses of LL-37 in group 1; however, mortality increased in group 2. In group 1, OAS and RT deteriorated initially for those receiving lower doses of LL-37, then improved. OAS and RT did not deteriorate throughout the study in rats given higher doses of LL-37. In group 2 rats given higher doses of LL-37, OAS and RT were not significantly different from rats in group 3. CRP was significantly decreased in group 1 compared with group 3, and decreased in group 2 for lower doses only. We conclude that LL-37 may prevent sepsis and be useful in lower doses for treating sepsis. However, LL-37 appears to have adverse effects when used at higher doses for treating sepsis.