Liver regeneration factor belongs to the leucinezipper family of transcription factors. It was originally cloned and characterized through differential screening of a regenerating rat liver cDNA library. The mRNA for liver regeneration factor-1 is barely detectable in normal rat liver but is dramatically induced after two-thirds hepatectomy, with a peak 1 to 3 hr after surgery. The nature of the signaling molecule(s) for this rapid induction is not known. It has been suggested that the liver regeneration factor-1 protein product, through complex interactions with other transcription factors such as c-Jun and Jun-B, controls expression of genes that are required during the G1 phase of hepatic growth. Hepatocyte growth factor has been shown to be the most potent mitogen for hepatocytes in vitro and in vivo. Plasma levels of hepatocyte growth factor rapidly (within 30 min) increase after loss of hepatic parenchyma induced by partial hepatectomy or carbon tetrachloride treatment. It has been postulated that hepatocyte growth factor plays a crucial role in stimulating the hepatocyte to enter the cell cycle. In this communication, we report that addition of pure hepatocyte growth factor to primary cultures of rat hepatocytes in the absence of serum and insulin results in rapid and transient induction of liver regeneration factor-1 mRNA (more than 20-fold) with a peak of expression 1 hr after treatment. The levels of jun-B and c-fos mRNAs, which are also known to be induced during the early hours of liver regeneration, were also increased after treatment of isolated hepatocytes with hepatocyte growth factor. Epidermal growth factor, another potent hepatomitogen, induced liver regeneration factor-1 mRNA with time kinetics similar to those of hepatocyte growth factor; however, the magnitude of induction by epidermal growth factor was much lower than that of hepatocyte growth factor. Hepatocyte growth factor and epidermal growth factor quickly (1 to 2 hr) increased the levels of mRNAs for two other immediate early genes, namely, early growth response gene-1 and insulin-like growth factor binding protein-1 in cultured hepatocytes. These two genes are known to be up-regulated during the early hours of liver regeneration. Taken together, our results support the notion that, in vivo, hepatocyte growth factor and epidermal growth factor play important functions in triggering and initiating the early events required for subsequent hepatocyte growth and liver regeneration. (Hepatology 1994;20:955–960).