The protective effects of hydroxyethyl starch-conjugated deferoxamine (HES-DFO), a macromolecular iron chelator, on the initial pathophysiological cascade in septic shock were evaluated following cecal ligation puncture (CLP) in rats. Animals were given an intravenous dose of 3.0 mL of either vehicle (HES) or HES-DFO immediately following completion of the CLP procedure. Animals were sacrificed 30, 60, 120, and 240 min following CLP, and samples of lung, kidney, bowel, and liver were collected for subsequent analysis of glutathione, myeloperoxidase, and evidence for lipid peroxidation based on measurement of thiobarbituric acid reactive substances and conjugated dienes. In addition, the endotoxin levels were determined in the plasma and histomorphological examination was conducted on tissue samples collected at each time point. At almost all time points, a reduction in lipid peroxidation was noted in the HES-DFO-treated rats (p < .05). Glutathione and myoloperoxidase levels were less affected. Lung tissue from animals receiving HEs demonstrated marked microatelectases, septal destruction, and splicing of basal membranes, which were greatly attenuated in animals having received HES-DFO. Similarly, tubulotoxic and mitochondrial damages observed in kidney samples from HES-treated animals were noticeably reduced in the animals having received the chelator. Liver and gut samples demonstrated unspecific inflammatory injury in both groups of animals. In summary, oxygen radical-mediated tissue damage occurs rapidly following CLP-induced sepsis. Based on histological and biochemical endpoints, treatment with the polymeric iron chelator, HES-DFO, significantly attenuates systemic oxidant injury, the degree of protection being most impressive in the lung and kidney.