Non-invasive serum markers of extensive liver fibrosis are required in clinical practice for several reasons: (1) although histological analysis is considered to be the gold standard for the diagnosis of extensive fibrosis and cirrhosis, the rate of false-negative results is approximately 15-20%; (2) liver biopsy is an invasive method with a 1/10 000 mortality rate, even though occurrence of death is exceptional in patients with diffuse liver disease; (3) patients with chronic viral hepatitis have to undergo multiple liver biopsies during follow-up to assess the progression of tissue injury. In this leading article, we briefly overview the recent progress in non-invasive serum markers for the prediction of the extent of liver fibrosis. Among those serum markers, we focused on prothrombin index, which seems to be a reliable and non-expansive marker for the diagnosis of extensive fibrosis.