Objective To explore the relationship between social support, self-disclosure and fatigue in patients with chronic liver failure, and to provide reference for taking targeted measures to reduce patients′ fatigue. Methods A total of 126 patients with chronic liver failure were surveyed using the general information questionnaire, Multidimensional Fatigue Scale-20, revised Distress Disclosure Index, and Perceived Social Support Scale. Results The social support score of patients with chronic liver failure was 56.30±5.96, the fatigue score was 58.39±3.15, and the self-disclosure score was 36.79±2.45. The social support of patients was positively correlated with self-disclosure and negatively correlated with fatigue (both P<0.05). Social support partially mediated the relationship between self-disclosure and fatigue, and the mediating effect accounted for 34.59% of the total effect. Conclusion Self-disclosure of patients with chronic liver failure has a direct predictive effect on fatigue, and social support plays a partial mediating role between self-disclosure and fatigue. Promoting patient self-disclosure and improving social support are effective ways to reduce patients′ fatigue.