ObjectivesTo determine the safety, pharmacokinetics, and activity of an anti-tumor necrosis factor (TNF)-α monoclonal antibody in severe sepsis. DesignOpen-label, prospective, phase II multicenter trial with escalating doses of a murine monoclonal antibody (CB0006). SettingTwelve academic medical center intensive care units in the United States and Europe. PatientsEighty patients with severe sepsis or septic shock who received standard supportive care and antimicrobial therapy in addition to the anti-TNF antibody. InterventionsPatients were treated intravenously with one of four dosing regimens with CB0006: 0.1 mg/kg, 1.0 mg/kg, 10 mg/kg or two doses of 1 mg/kg 24 hrs apart. Measurements and Main ResultsThe murine monoclonal anti-TNF antibody was well tolerated despite the development of anti-murine antibodies in 98% of patients. No survival benefit was found for the total study population, but patients with increased circulating TNF