Glucocorticoids and hepatocyte-stimulating factor (HSF; a monocyte/macrophage-derived polypeptide) are potent regulators of fibrinogen biosynthesis. Using primary rat hepatocytes and a rat hepatoma cell line (FAZA) we have determined, more precisely, the interaction between these two molecules in the control of fibrinogen production. When dexamethasone (DEX) or HSF is added to the cells, there is a substantial increase in fibrinogen production (1.5-3-fold). However, if both agents are administered simultaneously the response is much greater with a 15-20-fold rise in synthesis. Quantitative RNA analysis demonstrates that when the factors are present individually only HSF elevates fibrinogen mRNA levels, but the effect is much enhanced in the presence of DEX. This pattern is also seen in the results of the in vitro transcription assays which allow quantitation of mRNA synthesis in isolated nuclei. Cycloheximide does not significantly interfere with the increased transcription brought about by HSF in either cell type. However, the DEX enhancement is blocked by cycloheximide in FAZA cells, thus indicating that in the transformed cell protein synthesis is required for maximal transcription to occur. Data presented here demonstrates the requirement for two types of regulator molecules in the control of fibrinogen gene expression; a polypeptide hormone (HSF) that increases transcription and a steroid (DEX) that enhances the action of the polypeptide.