Abstract： Objective To investigate the protective effects of thalidomide on rats with acute necrotizing pancreatitis (ANP) and its mechanism. Methods Fifty four SD rats were randomly divided into the three groups; ANP group, thalidomide group and control group with 18 rats in each group. The model of ANP was induced by retrograde injection of 5% sodium taurocholate into the bili-pancreatic duct. Rats in thalidomide group received thalidomide 200 mg/kg body weight gastric lavage 1 h after ANP induction. The rats were sacrificed 3 h, 6 h, and 12 h after ANP induction, and the amount of intraperitoneal ascites was quantified. The serum levels of TNF-α, IL-6, IL-18 were measured by EUSA. The proportion of CD4 + T cell, CD8 + T cell in peripheral blood was determined by flow cytometry. The expression of TNF-α mRNA in pancreatic tissue were measured by RT-PCR. The expression of ICAM-1 protein in pancreatic tissue was measured by immunohistochemistry. Pancreatic tissue underwent pathologic examination. Results Six hours after surgery, the amount of ascite, serum levels of TNF-α, IL-6, IL-18, CD4 + T cell, CD,+ T cell, pancreatic TNF-α mRNA and ICAM-1 protein expression, pathologic score in control group was (1.03 ±0.31)ml,(57.17±11.29)pg/ml, (24.45 ±4.14)pg/ml, (64.23 ±21.85)pg/ml, (47.58 ±9.21)% , (40.88 ± 2.96)%, 0.07 ±0.02, 0.57 ±0.30, 0.67 ±0.81, respectively, and the corresponding values were (3.63 ± 0.38)ml, (107.54 ±33.05) pg/ml, (47.30 ± 11.40) pg/ml, (367.76 ± 108.43 ) pg/ml, (54.90 ± 7.15)%, (17.17 ±3.12)%, 0.65 ±0.26, 3.20 ±0.57, 11.50 ±1.87 in ANP group; and (1.45 ±0.53)ml, (80.60 ±20.48) pg/ml, (26.61 ±10.85) pg/ml, (321.82 ±85.20) pg/ml, (29.80 ±2.19)% , (15.52± 1.96)%, 0.35 ±0.23, 2.37 ±0.67, 8.00 ±3.03. Besides the value of CD8 + T cell was significantly decreased, all other values were significantly increased when compared with control group (P <0.05). Conclusions Thalidomide can decrease the release of inflammatory mediator, and reduce the pathological damage of pancreas of ANP rats by inhibiting TNF-α mRNA expression.