Hepatocyte growth factor (HGF) is mitogenic for hepatocytes and some tumor cell lines. Elevations in plasma HGF levels have been detected in patients with hepatocellular carcinoma (HCC), and it is possible that HGF is involved in the promotion and/or progression of tumor growth. We measured serum and liver tissue HGF levels during chemically induced hepatocarcinogenesis. Wistar rats were given diethylnitrosamine (DEN) in drinking water for 10 weeks with controls receiving drinking water only. Animals were killed at 10, 16, and 19 weeks. Liver HGF levels were determined from immunoblotted protein by scanning densitometry, and serum HGF levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). HGF was also immunolocalized in fixed liver tissue sections. In DEN-treated animals, at 10 weeks, there was necroinflammation but no dysplasia. Serum HGF was elevated compared with controls (P < .001) but there was no increase in liver HGF. At 16 weeks, there was liver cell dysplasia with minimal necroinflammation; serum and tissue HGF levels were both significantly elevated above controls. At 19 weeks, hepatocellular carcinomas (HCC) were present in five of six DEN-treated animals; liver HGF (P < .05) and serum HGF (P < .001) were both elevated compared with controls. HGF was localized in basement membranes around bile ducts and vessels and some perisinusoidal cells. Increased HGF immunolabeling was observed at 16 and 19 weeks, but dysplastic hepatocytes and tumor cells were HGF-negative. HGF may serve as a growth promoter at early stages during liver tumor development acting through possibly endocrine and paracrine pathways. Recent observations have described HGF as being mitoinhibitory for HCC cell lines; it is possible therefore that the continued up-regulation of HGF in the latter stages of our DEN model may inhibit tumor cell growth, and thus represent a form of antitumor host response.