We investigated the effects of the xanthine derivative propentofylline on lung injury in rats with cerulein-induced acute pancreatitis and endotoxemia. Pancreatitis was induced by four intramuscular injections of cerulein (50 μg/kg at 1-h intervals). Pancreatitis rats were injected intraperitoneally with 30 mg/kg lipopolysaccharide (LPS) 6 h following the first cerulein injection as a septic challenge. Propentofylline (50 mg/kg) was injected intravenously 15 min before the administration of LPS. Rats were divided randomly into five experimental groups: group I, normal rats; group II, pancreatitis; group III, LPS injection; group IV, pancreatitis and LPS injection; and group V, pancreatitis and LPS injection with propentofylline pretreatment. Serum amylase concentrations in groups II, IV, and V increased significantly 8 h after the first cerulein injection compared to those in groups I and III. Serum tumor necrosis factor (TNF)-α concentrations, cytokine-induced neutrophil chemoattractant (CINC) concentrations in serum or bronchoalveolar (BAL) fluid, lung myeloperoxidase (MPO) activity, and extent of pulmonary polymorphonuclear cell infiltration in group IV were significantly higher than those observed in group III. Pretreatment with propentofylline inhibited the rise in TNF-α levels (group V). However, propentofylline did not prevent the elevation of CINC levels in group V. In contrast, propentofylline reduced lung MPO and pulmonary PMN infiltration in group V. In addition, lung compliance was improved by pretreatment with propentofylline. These results suggest that propentofylline attenuates lung injury in an experimental model of pancreatitis complicated by endotoxemia but has differential effects on cytokine production.