We determine whether the serum KL-6/MUC1 (KL-6) levels in patients with type C liver disease can be used to assay inflammatory activity and the stage of fibrosis of patients, as well as to screen high-risk groups for the development of hepatocellular carcinoma (HCC). Study subjects included 130 patients with type C chronic hepatitis (CH), 15 patients diagnosed with type C acute hepatitis (AH) and 17 healthy control subjects. Frozen serum samples were obtained from each subject to determine the KL-6 levels using an enzyme-linked immunosorbent assay (EIA) method. The mean KL-6 levels in patients were as follows: 150.1 U/ml for healthy controls, 203.7 U/ml for AH patients, 225.7 U/ml for F0 stage, 207.4 U/ml for F1 stage, 235.8 U/ml for F2 stage, 193.3 U/ml for F3 stage, and 276.2 U/ml for F4 stage in CH patients. The mean serum KL-6 level in patients with F4 stage was significantly higher than that in healthy controls. No relationship was observed between the serum KL-6 levels and liver histology. However, the degree of irregular regeneration (IR) of hepatocytes and the levels of KL-6 were significantly correlated according to the progression of F stages. The cumulative incidence of HCC in the high KL-6 level group (>/=300 U/ml) was significantly greater than that in the low level group. Our results suggest that the determination of serum KL-6 levels may be useful in screening high-risk groups for the development of HCC.