In liver grafts that will fail as a result of storage injury, reperfusion activates Kupffer cells. Overproduction of tumor necrosis factor by activated Kupffer cells may cause primary graft nonfunction, multiple organ failure and, eventually, death of graft recipients. Carolina rinse solution, adenosine, nisoldipine, pentoxifylline and prostaglandin E₁ reduce graft failure from storage/reperfusion injury. To test the hypothesis that these agents act by suppressing cytokine release by activated Kupffer cells, we assessed the effect of each drug on tumor necrosis factor released from cultured rat Kupffer cells stimulated with lipopolysaccharide. Adenosine, nisoldipine and prostaglandin E₁ each suppressed lipopolysaccharide‐stimulated tumor necrosis factor release. The adenosine A₂ receptor agonists. 5‐n‐ethylcarboxamidadenosine, 2‐chloro‐adenosine and R‐phenylisopropyl adenosine also blocked tumor necrosis factor release in a potency suggestive of A₂ receptor activity. Xanthine amine congener, a specific A₁ receptor antagonist, failed to reverse the suppression by adenosine of tumor necrosis factor release, whereas CGS15943A, an A₂ receptor antagonist, did reverse suppression by adenosine and 5‐n‐ethylcarboxamidadenosine. CGS15943A had no effect on suppression of lipopolysaccharide‐stimulated tumor necrosis factor release by nisoldipine or prostaglandin E₁. Dibutyryl‐cyclicAMP also suppressed tumor necrosis factor release. Adenosine, 5‐n‐ethylcarboxamidadenosine, prostaglandin E₁ and pentoxifylline increased cyclicAMP levels in cultured Kupffer cells, but nisoldipine did not. We conclude that (a) adenosine A₂ receptors exist on Kupffer cells, (b) the suppression of tumor necrosis factor release by adenosine occurs by way of a cyclicAMP‐dependent adenosine A₂ receptor mechanism, (c) prostaglandin E₁ and nisoldipine also suppress tumor necrosis factor release but do not act through adenosine receptors and (d) because agents that suppress tumor necrosis factor release by Kupffer cells also reduce graft failure after liver transplantation, activation of Kupffer cells and release of tumor necrosis factor may be involved in storage/reperfusion injury to liver grafts. (HEPATOLOGY 1994;19:1445–1452.)