Background Erythropoietin (EPO) elicits protective effects in lung ischemia-reperfusion, hyperoxia, acute necrotizing pancreatitis, and some other tissues. In the present study, we investigated the possible protective roles of EPO in the lipopolysaccharide (LPS) induced lung injury. Materials and Methods Male Sprague-Dawley rats were treated with EPO (3000 U/kg, i.p.) or vehicle (saline), 30 min prior to LPS administration (6 mg/kg, i.v.). Four h following LPS injection, samples of pulmonary tissue were collected. Optical microscopy was performed to examine pathological changes in lungs. Validated methods were used to measure wet/dry ratios (W/D), myeloperoxidase (MPO) activity, malondialdehyde (MDA) concentrations, and nitrite/nitrate (NO 2 –/NO 3 –) levels in lungs. Western blotting was performed to study the pulmonary expression of inducible nitric oxide synthase (iNOS) and nitrotyrosine protein. Results Pretreatment with EPO led to (1) significant attenuation of endotoxemia induced evident lung histologic injury and edema; (2) inhibition of LPS mediated induction in MPO activity and MDA concentration; (3) inhibition of LPS mediated overproduction of pulmonary NO 2 –/NO 3 – levels; and (4) marked suppression in endotoxin induced expression of iNOS and nitrotyrosine. Conclusions This study provides considerable evidence that EPO has an ability to significantly attenuate endotoxin-induced acute lung injury in rats.