Nonalcoholic steatohepatitis (NASH) has gained attention as a hepatic manifestation associated with metabolic syndrome and one of the causes for chronic liver damage leading to hepatocellular carcinoma. Although no standard medicinal treatment for NASH has been established, pentoxifylline (PTX), a medicine used to improve circulation, has recently been reported to ameliorate the histopathological appearance of NASH. In the present study, we investigated the effects of PTX on the development of NASH and diethylnitrosamine-induced liver tumorigenesis in C57BLKS/J- +Lepr(db)/+Lepr(db) obese and diabetic mice, which are considered a rodent model for NASH-related hepatocarcinogenesis. Mice were administered diethylnitrosamine, and then they received water with or without PTX. At the time of sacrifice, the development of hepatic pre-neoplastic lesions was significantly suppressed in the PTX groups. Hepatic triglyceride contents were decreased by PTX administration. The serum levels of triglyceride, free fatty acid, and alanine aminotransferase were all decreased by PTX treatment, as was the mRNA expression of proinflammatory cytokines, macrophage-inducing chemokines, and several lipogenic genes in the liver. In-vitro studies also showed that PTX treatment decreased the expression of several lipogenic genes and chemokines in cell lines. These findings suggest that PTX prevents NASH-related liver tumorigenesis by attenuating chronic hepatic inflammation and decreasing lipogenic gene expression in the liver. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.