To clarify the mechanism involved in regulating the secretion of albumin and alpha 1-acid glycoprotein by rat hepatocytes, we studied hepatocyte culture and cocultures of hepatocyte and liver nonparenchymal cells. The secretion of alpha 1-acid glycoprotein by hepatocytes was stimulated and that of albumin was inhibited by combinations of dexamethasone and monokines, especially by dexamethasone and interleukin-6. The secretion of these proteins was equally inhibited during stimulation by lipopolysaccharide in cocultures. The inhibitory effect of sinusoidal endothelial cells was smaller than that of Kupffer cells. This inhibition was partially abolished by blocking the nitric oxide synthase pathway in cocultured cells and was completely abolished by dexamethasone. In conclusion, the secretion of albumin and alpha 1-acid glycoprotein by hepatocytes was regulated by monokines, dexamethasone, and the inducible nitric oxide synthase pathway in hepatocytes and liver nonparenchymal cells in vitro.