Kupffer cell control of hepatocyte protein synthesis may be an important mechanism involved in the regulation of normal liver function and may be one mechanism responsible for the alterations in liver function seen during sepsis. The present series of in vitro experiments compare the response to various inflammatory stimuli of hepatocytes cocultured with Kupffer cells with that of hepatocytes cultured alone. In the absence of inflammatory stimuli, Kupffer cells stimulated hepatocyte protein synthesis. Lipopolysaccharide or gentamicin-killed Escherichia coli triggered Kupffer cell-mediated inhibition of cocultured hepatocyte protein synthesis but had no effect on protein synthesis of hepatocytes cultured alone. Phorbol myristate acetate, muramyl dipeptide, and calcium ionophore had no effect on hepatocytes cultured alone but resulted in a loss of Kupffer cell-mediated stimulation of cocultured hepatocyte protein synthesis without inhibition. Addition of dexamethasone to cocultures prevented the Kupffer cell-mediated inhibition of hepatocyte protein synthesis triggered by lipopolysaccharide, but did not block Kupffer cell-mediated stimulation in the absence of lipopolysaccharide. The data suggest that Kupffer cells can stimulate and inhibit hepatocyte protein synthesis by independent mechanisms. Kupffer cells may be important regulators of hepatocellular function in health and disease.