OBJECTIVES: the impact of liver diseases (LDs) on health-related quality of life (HRQoL) is an important aspect to understand the burden of these conditions and improve their management. A well characterized impact of the major LDs on HRQoL of the general population is still lacking. The aim of our study was to fill this GAP. METHODS: a dataset with HRQoL data of a representative sample of the general population of most populated Italian region was matched with the dataset from a multicenter study conducted in the same region and time period to generate and validate a set of health care outcomes indicators for the major LDs (hepatitis B (HBV), hepatitis C (HCV), compensated cirrhosis (CC), decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), NAFLD/NASH and patients listed for liver transplant (LTL)). Within both datasets, HRQoL data were collected using the EQ-5D-3L. Multivariate logistic and Tobit regressions were then performed adjusting for possible confounders (age, sex, education and working status).  RESULTS: a total of 6,800 “healthy subjects” and 3,105 subjects with LDs were included in the analyses. Multivariate logistic analyses showed that DC, HCC, and LTL had significantly (p<0.05) higher risk to have problems in mobility, self-care, and usual activities compared to “healthy subjects”. AIH had significantly higher risk to have problems in self-care; while HCV, CC, DC, and NAFLD/NASH in Anxiety/depression. Similar results were obtained with the Tobit model performed using VAS and Utility-index. DC, HCC, AIH and LTL reported the highest decrease in VAS and Utility score.  CONCLUSIONS: HRQoL decreased in advanced LDs (DC, HCC, LTL) and AIH. This study provides an actual true estimate of the impact of major LDs on the patients’ HRQoL compare to the general population, and therefore is a key tool for decision-making in care delivery for liver diseases.