Purpose: There are only a few measures to assess quality of life among patients with liver disorders. The aim of this study was to determine the psychometric properties of the Liver Disease Symptom Index Version 2.0 (LDSI 2.0), a disease specific measure of health-related quality of life (HRQOL), in Persian-speaking patients with chronic hepatitis B. Method: Using a cross-sectional design, 312 patients were recruited. Data were collected from the patients using the LDSI 2.0, Chronic Liver Disease Questionnaire, and EuroQol. Convergent and discriminant validity were investigated. Known-groups validity and factor structure of the scale were also determined. Receiver operating characteristics was used to discriminate patients based on their general health status. Results: Significant correlations were found between HRQOL measures. Disease duration, disease stage, and serum aspartate aminotransferase differentiated patients. Factor analysis determined a seven-factor solution that explained 70% of the total variance. Area under the curve in receiver operating characteristics analysis was 0.706; 95% confidence interval = [0.648, 0.764]. Conclusions: The LDSI2.0 is an appropriate HRQOL scale for use among Iranian patients with chronic hepatitis B based on its solid psychometric properties in this population.