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End-stage liver disease (ESLD) patients are believed to have a high prevalence of depression, although mental health in ESLD has not been studied comprehensively. Further, the relationship between depression and severity of liver disease is unclear. Using baseline data from a large prospective cohort study (N = 500) of frailty in ESLD patients, we studied the association of frailty with depression. Frailty was assessed with the five-component Fried Frailty Index. Patients were assigned a composite score of 0 to 5, with scores ≥3 considered frail. Depression was assessed using the 15-question Geriatric Depression Scale, with a threshold of ≥6 indicating depression; 43.2% of patients were frail and 39.4% of patients were depressed (median score 4, range 0–15). In multivariate analysis, frailty was significantly associated with depression (odds ratio 2.78, 95% confidence interval 1.87–4.15, p < 0.001), whereas model for ESLD score was not associated with depression. After covariate adjustment, depression prevalence was 3.6 times higher in the most-frail patients than the least-frail patients. In conclusion, depression is common in ESLD patients and is strongly associated with frailty but not with severity of liver disease. Transplant centers should address mental health issues and frailty; targeted interventions may lower the burden of mental illness in this population.This study suggests that depression in end-stage liver disease patients is prevalent and strongly associated with frailty but not with severity of liver disease.