Septic shock is caused by a systemic inflammatory response resulting in hypotension, myocardial depression, multiple organ failure and death. Nitric Oxide (NO) is a potent vasodilator, and inhibition of NO synthases (NOS) increases systemic vascular resistance and blood pressure in shock1. Nevertheless, NO also exerts protective roles, as NOS inhibitors worsen and certain NO donors ameliorate shock.1-3 We study inflammatory shock using I.V. Tumor Necrosis Factor (TNF), lipopolysaccharide (LPS), or other TLR agonists in female C57BL/6 mice. Expression of inducible iNOS, as well as systemic NO accumulation, were not correlated with cardiovascular failure, morbidity or mortality, indicating that inflammation-induced NO is not sufficient to cause shock. In contrast, cardiovascular collapse (hypotension, bradycardia, loss of cardiac contractility) and mortality were completely reversed by tempol, a cell-permeable radical scavenger (100% survival vs. 0%, p<0.001, Log-Rank test), indicating a decisive role for ROS rather than NO. Protection by tempol was dose dependent (100-300 mg/kg I.P.) and could be achieved by pre- or post-treatment (-45 to +15 min). For cardiovascular analysis, we used PA-C10 or HD-X11 radio-transmitters (Data Sciences International) implanted under isoflurane anesthesia. Mitochondria may be important sources and targets of ROS. Following TNF or LPS, we found evidence for ROS-mediated damage to mitochondrial complexes. Nevertheless, although the mitochondria-targeted antioxidant mitoQ (5-10 mg/kg, I.P. or I.V.) could partially protect against early morbidity (hypothermia), it did not prevent mitochondrial and necrotic damage (measured via complex I activity in homogenized livers and lactate dehydrogenase activity in plasma, respectively), or cardiovascular failure. Our results thus indicate that ROS radicals are critically involved in the induction and progression of inflammatory cardiovascular collapse, and mitochondrial and necrotic damage. However, using a hyperacute shock model associated with excessive oxidative stress4, we also found evidence for a protective role of certain ROS, presumably H2O2, as catalase treatment both aggravated the hyperacute shock and reduced the long-term protective capacity of tempol.5 In conclusion, our results change the current paradigms on NO and ROS in inflammatory cardiovascular dysfunction. While NO seems predominantly protective, we found evidence for both detrimental and protective ROS effects. Hence, selective antioxidants may be a promising therapy to protect against inflammation-associated cardiovascular, mitochondrial and necrotic damage. Since mitoQ cannot reproduce the protective effects of tempol, we hypothesize that other sources of ROS (e.g. NADPH oxidases) may be involved in the detrimental effects, or that mitochondrial ROS is involved in protective pathways.