The purpose of this study was to determine whether prevention of Kupffer cell activation following orthotopic liver transplantation improves postoperative survival. First, particle phagocytosis by Kupffer cells was monitored continuously from the uptake of colloidal carbon by the perfused liver. Unstored livers took up carbon at rates of around 150 mg/g per hour, whereas storage for 24 h in Euro-Collins solution nearly doubled values to about 290 mg/g per hour. Treatment of rats with methyl palmitate, an inhibitor of phagocytosis by Kupffer cells, reduced carbon uptake to about one-third to one-half of control values in unstored and stored livers, respectively. Oxygen uptake, which was increased about 25% in stored and unstored livers by infusion of colloidal carbon, was only increased 5%-10% in both groups following treatment with methyl palmitate, suggesting that Kupffer cell activation was prevented by methyl palmitate. In livers transplanted after storage for 6 h in Euro-Collins solution (nonsurvival conditions), control rats survived only about 12 h, while treatment with methyl palmitate increased survival time significantly--more than threefold--to about 40 h. These data are consistent with the hypothesis that activation of Kupffer cells following cold ischemic storage and reperfusion is an early event involved in liver graft failure.