To clarify the link between cytotoxic damage to the hepatocyte and the development of fibrosis, we immunoenzymatically measured serum prolyl hydroxylase (hPH), type IV collagen (CL-IV) and circulating intercellular adhesion molecule-1 (clCAM-1). The population studied was comprised of 122 patients with liver disease (acute hepatitis; mild chronic liver disease; cirrhosis; hepatocellular carcinoma) and 33 patients with extrahepatic diseases. Similar patterns were observed for hPH, CL-IV, and clCAM-1, that were higher in patients with acute hepatitis and hepatocellular carcinoma than in those with mild chronic liver disease (Bonferroni's test for pairwise comparisons, p < 0.01). Liver function tests and markers of fibrosis showed a strict correlation, which disappeared when the linear effect of clCAM-1 was removed. The ability to predict serum hPH and CL-IV from clCAM-1 might suggest the existence of a causal relationship between fibrosis and targeting of cytotoxic damage.