This study was designed to investigate the protective effect and possible mechanisms of swertiamarin against sepsis-induced acute lung injury (ALI) in rats. Sepsis was induced by cecal ligation and puncture (CLP). The pulmonary gas exchange function (PaO2/FiO(2) ratio) and the lung water content [lung wet/dry weight (W/D) ratio] were measured by blood-gas analyzer and analytical balance. The blood capillary membrane permeability indices (neutrophils and lymphocytes counts and protein content) and the levels of inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6 and IL-10) in bronchoalveolar lavage fluid of rats were determined by light microscopy and Elisa. The oxidative stress parameters [activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and levels of malondialdehyde (MDA) and glutathione (GSH)], the activity of myeloperoxidase (MPO) and the levels of NF-kappa B p65, p-IKK alpha/beta (Ser 180/Ser 181) and I kappa B alpha proteins in lung tissue of rats were determined by Elisa and western blot. The survival rate of rats with CLP-induced ALI were recorded and analyzed by survival analysis method. The results indicated that swertiamarin significantly increased the PaO2/FiO(2) ratio, the activities of SOD and GSH-Px, the levels of IL10, GSH and I kappa B alpha and decreased the lung W/D ratio, the neutrophils and lymphocytes counts, the protein content, the activity of MPO, the levels of TNF-alpha, IL-1 beta, IL-6, MDA, NF-kappa B p65 and p-IKK alpha/beta (Ser 180/Ser 181). Benefiting from these changes as described above, the survival rate of rats with CLP-induced ALI was significantly increased after treatment with swertiamarin. In conclusion, swertiamarin showed protective effect against CLP-induced ALI in rats, and the mechanisms of action might be related to reducing blood capillary membrane permeability, inhibiting inflammatory response and increasing anti-oxidant ability in lung of rats with CLP-induced ALI.