Abstract: OBJECTIVE To prepare 4-(5'-dimethylamino)-naphthalenesulfonyl-2(3H)-benzoxazolone(W3D) as solid dispersion to investigate its protective effect on N-acetyl-para-aminophenol(APAP) induced acute liver injury(ALI). METHODS The solid dispersion of W3D was prepared by the reaction of W3D and PVP k30 at a ratio of 1:7 using solvent method. Differential scanning calorimetry(DSC) and X-ray diffraction(XRD) analysis were used to characterize the phase change of the solid dispersion. The saturation solubility and dissolution reproducibility were also determined. After APAP induced ALI model mice established, the mice were administered intragastrically with n-acetyl-L-cysteine(NAC), W3D(12.5 mg·kg^-1), W3D solid dispersion (12.5, 6.25 and 3.125 mg·kg^-1). Twenty-four hours later, the liver tissues were collected to calculate the liver index, and the pathological changes were evaluated by HE staining. The expression of ALT and AST in serum, SOD activity and GSH in liver tissue were detected by microporosity plate, MDA content was detected by TBA method, TNF-α and IL-6 contents in serum were detected by ELISA, and the expression of MD2 protein in liver tissue was detected by immunohistochemistry. RESULTS The W3D solid dispersion was amorphous and the dissolution rate was ＞70% in 10 min. W3D could decrease the liver index, reduce the phenomenon of nucleus pycnosis, fragmentation and dissolution compared with APAP treated group. The levels of ALT, AST, TNF-α and IL-6 in serum were decreased dose-dependently, and the activities of GSH and SOD in liver tissue were increased in W3D treat groups. On the contrary, W3D could reduce the production of MDA significantly, which was better than NAC. Meanwhile, the expressions of MD2 protein in liver tissues were also decreased after the treatment of W3D. CONCLUSION W3D solid dispersion can protect APAP-induced ALI by regulate the oxidative stress and inflammation reaction, and the mechanism might be related to the inhibiting effect on MD2 protein.