Acute pancreatitis (AP) is considered one of the typical conditions causing systemic inflammatory response (SIRS). Systemic complications are the most important contributors to multiple organ failure and death during the first stages of severe acute pancreatitis. Levels of pro-inflammatory cytokines increase during the course of AP, and these levels appear to be correlated with the severity of pancreatic inflammation. TNF-a may be an initiator of inflammatory process in AP. Previous studies using pentoxifylline to block TNF-a production has showed good benefits in experimental models of sepsis and shock. The gut is a target organ of the SIRS causing gut barrier dysfunction allowing bacterial and toxin translocation. Aim: To determinate the effects of inhibition of TNF-a on the pancreatic and systemic inflammatory response, pancreatic infection, and mortality rate in necrotizing acute pancreatitis in rats. Methods: An experimental model of severe AP by injection of 0.5m1 of 2.5% sodium taurocholate into the pancreatic duct was utilized. Ninety male wistar rats were divided in 3 groups: Sham (surgical procedure without AP induction) , Pancreatitis (AP Induction) , and Pentoxifylline (AP induction plus administration of 25 mg/kg pentoxifylline). Pancreatic inflammatory response was measured by histological studies and systemic inflammatory response was analyzed measuring the production of inflammatory cytokines (IL-6, IL-10, and TNF-a). Pancreatic infection was evaluated with bacterial cultures performed 24 h after the AP induction. The numbers of organisms were expressed in co1ony forming units (CFU) per gram. The occurrence of pancreatic infection was also analyzed and considered positive when the CFU/g was > 105. The animals were kept alive for 7 days to study the mortality rate. Results: Inhibition of TNF-a by pentoxifylline shows beneficial effects in this experimental model. The Pentoxifyfline group had a statistically significant reduction of histological damage in the pancreas, inflammatory cytokines levels (IL-6, IL-10, and TNF-a) , and occurrence of pancreatic infection (p < 0.05). These changes were associated with a significant reduction of mortality rate. Conclusions: Inhibition of TNF-a reduced local and systemic inflammatory response, reduced systemic complication as pancreatic infection, and decrease mortality rate in this model. These findings provide a possible improvement in treatment of acute pancreatitis.