Previous research with pentoxifylline (n), a methylxanthine phosphodiesterase inhibitor, suggests that this drug may be capable of suppressing the activation of Kupffer cells and thereby help decrease liver injury after transplantation. To investigate this possibility, the current study sought to determine whether the release of 0, and tumor necrosis factor (TNF) from Kupffer cells in donor livers can be suppressed if the organs are exposed to PTX before preservation. In an in vitro experiment, rat livers were flushed with PTX (25 mgfkg body weight) in University of Washington (UW) solution or UW solution alone (control) and then and stored in UW solution for either 4 or 24 hours. Kupffer cells then were purified and their degree of activation determined by measuring O2 release and the production of TNF after lipopolysaccharide stimulation. In an in uivo experiment, a group of rats underwent orthotopic liver transplantation with grafts prepared in the same manner as in the in vitro study. TNF and aspartate transaminase (AST) were measured in blood samples taken 3 hours and 24 hours after transplantation. Compared with controls, the Kupffer cells from grafts pretreated with PTX produced significantly less 0; and TNF, and the recipients of =-pretreated grafts had lower levels of TNF and AST 3 hours after transplantation. The current data indicate that O2 and TNF production in liver grafts is suppressed by PTX pretreatment. Through its suppressive effect on Kupffer cells, PTX may help minimize preservation-reperfusion injury and improve graft survival. (HEPATOLOGY 1995;21:1079-1082.) Despite the longer periods of safe organ preservation now afforded by University of Washington (UW) solution,' preservation-reperfusion injury continues to be a major problem in liver transplantation. Reperfusion of the graft after the ischemic interval between procurement and transplantation causes a release of toxic Abbreviations: UW, University of Washington; TNF, tumor necrosis factor; PTX, pentoxifylline; AST, aspartate transaminase.