BACKGROUND There are no data about the frequency of major depression in patients with liver disease related to Hepatitis B virus (HBV) in China. This study examined the prevalence of major depression and its clinical correlates and association with quality of life (QOL) in patients with HBV-related liver diseases. METHOD Altogether 634 patients with HBV-related liver diseases met study entry criteria and completed the survey. The diagnosis of major depression was established with the Mini International Neuropsychiatric Interview (MINI). Socio-demographic and clinical characteristics, Global Assessment of Functioning (GAF) and QOL were measured. RESULTS The prevalence of major depression was 6.4%. Multivariable logistic regression analyses revealed that insomnia (P = 0.01, OR = 5.5, 95%CI = 1.4–21.6) and global functioning (P < 0.001, OR = 0.6, 95% CI = 0.5–0.7) were independently associated with major depression. Major depression was associated with both poor physical (F (1, 634) = 4.0, P = 0.04) and mental QOL (F (1, 634) = 26.2, P < 0.001). CONCLUSIONS Given the negative impact of depression on patients’ QOL, more attempts should be made to identify and treat it in HBV-related diseases.