The pathogenesis of chronic alcoholic liver disease is uncertain, but it may reflect an impaired wound healing response to ethanol-induced liver injury. Cellto-cell communication such as that mediated by the cytokine tumor necrosis factor is necessary for successful liver regeneration and complete recovery from liver injury. Hence disruption of intercellular regenerative signaling may contribute to the pathogenesis of chronic alcoholic liver disease. To test this hypothesis, the cytokine and regenerative responses triggered by partial hepatectomy were compared in ethanol-fed rats and isocalorically maintained, pair-fed controls. To further clarify the effect of ethanol on tumor necrosis factor–modulated regenerative effects, we evaluated some of the rats in each feeding group after pretreatment with antibodies to tumor necrosis factor. As expected, ethanol inhibited DNA synthesis and liver cell proliferation after partial hepatectomy. Ethanolassociated inhibition of liver regeneration occurred despite apparently similar serum concentrations of the tumor necrosis factor–inducible cytokine interleukin-6. Treatment with antibodies to tumor necrosis factor 1 hr before partial hepatectomy inhibited post–partial hepatectomy induction of interleukin-6 and liver regeneration in ethanol-fed and pair-fed rats. However, serum interleukin-6 was reduced more in ethanol-fed rats than in control rats (93% vs. 66%; p < 0.05). Antibodies to tumor necrosis factor also inhibited hepatic DNA synthesis more in ethanol-fed rats than in controls (85% vs. 50%; p < 0.05). In ethanol-fed rats, the increased effect of tumor necrosis factor antibody on post–partial hepatectomy DNA synthesis suggests heightened sensitivity of hepatocytes to tumor necrosis factor. Tumor necrosis factor antibody decreased hepatocyte proliferation more (93%) in ethanol-fed rats than in controls (62%) (p < 0.05). In contrast, proliferation of liver nonparenchymal cells was less inhibited in ethanol-fed rats(11%) than in controls (66%) (p <0.05). These data indicate that long-term ethanol feeding alters cell responsiveness to tumor necrosis factor during liver regeneration. Such ethanol-induced alterations in cell response to cytokines may disrupt intercellular communications and impede normal liver regeneration. (HEPATOLOGY 1993;17:1066–1073).