Introduction and objectives: Liver disease is characterized by the progression from hepatitis to cirrhosis, followed by liver cancer, i.e., a disease with a higher mortality rate as the disease progresses. To estimate the cost of illness (COI) of liver diseases, including viral hepatitis, cirrhosis, and liver cancer, and to determine the overall effect of expensive but effective direct-acting antivirals on the COI of liver diseases. Patients or materials and methods: Using a COI method from available government statistics data, we estimated the economic burden at 3-year intervals from 2002 to 2017. Results: The total COI of liver diseases was 1402 billion JPY in 2017. The COI of viral hepatitis, cirrhosis, and liver cancer showed a downward trend. Conversely, other liver diseases, including alcoholic liver disease and nonalcoholic steatohepatitis (NASH), showed an upward trend. The COI of hepatitis C continued to decline despite a sharp increase in drug unit prices between 2014 and 2017. Conclusions: The COI of liver diseases in Japan has been decreasing for the past 15 years. In the future, a further reduction in patients with hepatitis C is expected, and even if the incidence of NASH and alcoholic liver disease increases, that of cirrhosis and liver cancer will likely continue to decrease.