Our previous studies show that 2 microglobulin knockout mice treated with anti-asialoGM1 (2MKO/AsGM1 mice) are resistant to injury caused by cecal ligation and puncture (CLP). However, CLP-induced injury is complex. Potential mechanisms of injury include systemic infection, cecal ischemia and translocation of bacterial toxins such as endotoxin and superantigens. Currently, it is unclear which of these mechanisms of injury contributes to mortality in wild type mice and whether 2MKO/AsGM1 mice are resistant to any particular mechanisms of injury. In the present study, we hypothesized that systemic infection is the major cause of injury following CLP in wild type mice and that 2MKO/AsGM1mice are resistant to infection-induced injury. To test this hypothesis, wild type and 2MKO/AsGM1 mice were treated with the broad-spectrum antibiotic imipenem immediately following CLP to decrease the impact of systemic infection in our model. Treatment of wild type and 2MKO/AsGM1 mice with imipenem decreased bacterial counts at least 2 orders of magnitude. However, all wild type mice, whether treated with saline or imipenem, died by 42 hours after CLP and had significant hypothermia, metabolic acidosis and high plasma concentrations of the cytokines IL-6, MIP-2 and KC. 2MKO/AsGM1 mice showed 40% long-term survival, which was increased to 90% by imipenem treatment. 2MKO/AsGM1 mice had less hypothermia, decreased metabolic acidosis and lower cytokine concentrations at 18 hours after CLP compared to wild type mice. These results suggest that infection is not the major cause of mortality for wild type mice in our model of CLP. Other mechanisms of injury such as cecal ischemia or translocation of microbial toxins may be more important. 2MKO/AsGM1 mice appear resistant these early, non-infection-related, causes of CLP-induced injury but showed delayed mortality associated with bacterial dissemination, which was ablated by treatment with imipenem.