Background <p>The available evidence suggests an association between depression and single liver disease (e.g., chronic liver disease [CLD], metabolic dysfunction-associated steatotic liver disease [MASLD]), but its association with both multiple single specific liver diseases and major adverse spleen outcomes (MASO) has not been systematically evaluated. The aim of this study was to explore the association between depression and all ICD-10 three-digit coded liver diseases as well as MASO risk in the UK Biobank.</p> Methods <p>The data were obtained from the UK Biobank. Depression was assessed at baseline to determine whether participants were depressed. Diagnoses of depression, liver diseases, and MASO were based on hospital records, primary care records, and death records. Cox proportional hazard model was used to analyze the association between depression with eight specific liver diseases and MASO.</p> Results <p>This study included 384,074 participants (mean age 57.06 (SD 8.10) years, 45.68% male, 94.67% White). After adjusting for covariates, the HRs for the development of alcoholic liver disease, toxic liver disease, hepatic failure, fibrosis and cirrhosis of liver, other inflammatory liver diseases and other diseases of liver were 2.46 (95% CI: 2.12, 2.85), 1.92(95%CI: 1.17,3.16), 1.54 (95%CI: 1.25,1.89), 1.38(95%CI: 1.19,1.61), 1.27 (95%CI: 1.07,1.51) and 1.45 (95%CI, 1.37,1.52), respectively. Participants with depression had a 10% increased risk of developing MASO (HR, 1.10; 95% CI: 1.03,1.18).</p> Conclusion <p>Depression is significantly associated with the development of various specific liver diseases and MASO.</p>