Abstract: Objective To investigate the common etiology and clinical features of hepatomegaly of unknown origin. Methods A retrospective analysis was performed for the clinical data of 87 patients with hepatomegaly of unknown origin who were admitted to The Fifth Medical Center of Chinese PLA General Hospital from January 2009 to December 2018,including sex,age,clinical symptoms,signs,and laboratory markers. An analysis of variance was used for comparison of normally distributed continuous data between multiple groups,and the least significant difference t-test was used for further comparison between two groups; the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups and further comparison between two groups. For categorical variables,the chi-square test was used for comparison of categorical data between groups. Results Among the 87 patients,2(2. 30%) had unknown etiology,and 85(97. 70%) had a confirmed diagnosis based on pathology,among whom 18(20. 69%) had non-hepatotropic viral hepatitis,8(9. 20%) had chronic drug-induced liver injury,and 22(25. 29%) had glycogen storage disease. There were significant differences in age,sex,alanine aminotransferase,aspartate aminotransferase,white blood cell count,and platelet count between the non-hepatotropic viral hepatitis group,the chronic drug-induced liver injury group,and the glycogen storage disease group(χ2= 5. 80,10. 34,16. 85,18. 69,10. 02,12. 76,all P < 0. 05). According to the results of pathological examination,the patients with glycogen storage disease had typical plant cell-like arrangement with positive results of PAS staining; the patients with chronic drug-induced liver injury had disordered lobular structure and mixed inflammatory cell infiltration with a majority of polymorphonuclear leukocytes in the hepatic sinusoids; the patients with non-hepatotropic viral hepatitis mainly had liver parenchymal inflammation,disordered lobular structure,and pseudolobular structure in the early stage. Conclusion Hepatomegaly of unknown origin has complex etiologies,with inherited metabolic diseases as the most common cause,mainly glycogen storage diseases. Other causes such as non-hepatotropic viral hepatitis and chronic drug-induced liver injury arealso important causes of hepatomegaly of unknown origin.