The impact of depression on the risk of liver-related mortality in individuals with hepatitis B virus (HBV) infection remains unclear. We examined the association between depression, HBV infection, and liver-related mortality. A total of 342,998 Korean adults who underwent health examinations were followed for up to 7.8 years. Depressive symptoms were defined as a Center for Epidemiologic Studies-Depression score ≥ 16. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). During 1,836,508 person-years of follow-up, 74 liver-related deaths and 54 liver cancer deaths were identified (liver-related mortality rate of 4.0 per 105 person-years and liver cancer mortality rate of 2.9 per 105 person-years). Subjects with depressive symptoms had an increased risk of liver-related mortality with a corresponding multivariable aHR of 2.00 (95% CI 1.10-3.63) compared to those without depressive symptoms. This association was more evident in HBsAg-positive participants with a corresponding multivariable aHR of 4.22 (95% CI 1.81-9.88) than HBsAg-negative participants (P for interaction by HBsAg positivity = 0.036). A similar pattern was observed in relation to liver cancer mortality. In this large cohort, depressive symptoms were associated with an increased risk of liver-related mortality, with a stronger association in HBsAg-positive individuals.