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Objectives Fatigue is common in patients with chronic liver disease; however, its pathogenesis is unclear. This study aimed to provide insights into the pathogenesis of chronic liver disease-related fatigue by assessing the relationship between fatigue and the degree of inflammation in chronic liver disease.Design We performed a cross-sectional study of 1374 patients with pathologically proven chronic liver disease diagnosed at the Affiliated Hospital of Hangzhou Normal University in Hangzhou, China.Setting Primary single-centre study.Participants One thousand three hundred and seventy-four patients with liver biopsy-proven chronic liver disease.Interventions The patients were divided into fatigue and non-fatigue groups according to the Chronic Liver Disease Questionnaire. Propensity score matching was used to match the baseline features of the patients in the two groups.Primary and secondary outcome measures Liver steatosis, ballooning, inflammation and fibrosis were measured according to the pathological results of liver biopsy. Fatigue was measured using the Chronic Liver Disease Questionnaire.Results Of the 1374 patients, 262 (19.67%) experienced fatigue. There were 242 and 484 patients with and without fatigue, respectively, who were successfully matched for sex, age and classification of chronic liver disease by propensity score matching. After matching, the fatigue group showed higher liver enzyme levels, inflammation grades and fibrosis stages than the non-fatigue group (p<0.05). Multivariate analysis showed that age (OR: 2.026; p=0.003), autoimmune liver disease (OR: 2.749; p=0.002) and active inflammation (OR: 1.587; p=0.003) were independent risk factors for fatigue after adjusting for confounders. The OR of the risk for fatigue increased in a stepwise manner with increasing inflammation grade in young-aged and middle-aged patients (p<0.05). This tendency was not observed in elderly patients (p>0.05).Conclusion Patients with chronic liver disease were burdened by fatigue, which increased progressively with rising liver inflammation severity in young-aged and middle-aged rather than elderly patients.