Serum cytokeratin (CK) levels are widely used as tumor markers. Serum levels of CK-18, a tumor marker also known as tissue polypeptide specific antigen (TPS), are increased in patients with alcoholic liver disease. Cytokeratin-18 is the main component of Mallory bodies, a hallmark of alcoholic hepatitis, which may also contain CK-19. Serum levels of CK-18 and CK-19, a tumor marker also known as CYtokeratin FRAgment 21-1 (CYFRA 21-1) were investigated in (a) heavy drinkers with alcoholic liver disease (n=15), (b) patients with malignancy (n=22), and (c) healthy controls (n=10). Serum levels of CYFRA 21-1 (CK-19) were markedly increased in patients with malignancy, but were similar in heavy drinkers and healthy controls. In contrast, serum levels of TPS (CK-18) in heavy drinkers were higher than those of healthy controls, and even tended to be higher than those of patients with malignancy. Both CK-19 and CK-18 levels were higher in cases of alcoholic hepatitis than in cases of fatty liver. Correlation with hepatocyte CK inclusions was stronger for serum TPS (CK-18) than for CYFRA 21-1 (CK-19). In conclusion, serum CYFRA 21-1 (CK-19) and TPS (CK-18) show a different pattern of increase that could reflect the composition of the altered hepatocyte CK network in alcoholic liver disease. Their usefulness as tumor markers, particularly that of serum TPS (CK-18), may be limited in patients with alcoholic liver disease.