Different antibiotic treatments may affect the survival and physiological responses of Balb/c mice following cecal ligation and puncture (CLP). The broad spectrum imipenem (IMP) was compared with a triple antibiotic mixture of gentamicin, clindamycin, and ciprofloxacin (3AB). Control mice received injections of 5% dextrose (D5W). After CLP with a 25 gauge needle, Mini-Mitters were implanted to measure temperature and activity. Therapy began with 1 mL injections of antibiotics or D5W 2 h post-CLP and continued every 12 h for 3 days. Survival was higher in IMP mice than in 3AB or D5W mice. Starting with the injection 12 h after CLP, 3AB always induced a profound hypothermic response not observed with D5W or IMP. Nocturnal activity levels were higher in IMP mice compared with 3AB or D5W mice during the first night following CLP. To determine the cause of this hypothermic response and to further investigate the acute effects that antibiotic choice may have on murine physiology, the kinetic appearance of IL-1, IL-6, TNF, and KG as well as lipopolysaccharide (LPS), were measured in the plasma and peritoneum of mice sacrificed at 0,. 5, and 1.5 h after antibiotic injection at 24 h post-CLP. Cytokine and LPS concentrations in 3AB mice were not significantly different at any of the three time points when compared with IMP or D5W mice. Our data demonstrate that antibiotic therapy consisting of 3AB produces greater morbidity and mortality compared with therapy consisting of IMP. However, the mechanism of these alterations is not due to elevated systemic levels of cytokines or LPS.