AIM: To improve the awareness of liver injury of unknown causes by analyzing the diagnostic and pathological features of unexplained liver injury. METHODS: A total of 115 patients with liver injury of unknown reasons were enrolled in this study. The biochemical and immunological features, as well as virus markers, abdominal imaging findings and hepatic histopathology were analyzed. RESULTS: A definite diagnosis was achieved by liver biopsy in 109 patients. Among them, 38 were diagnosed with primary biliary cirrhosis (PBC), and the main pathological feature was non-suppurative inflammation in the bile duct; 31 with autoimmune hepatitis (AIH), which showed obvious interface inflammation in liver tissue; 27 with nonalcoholic fatty liver disease (NAFLD), which showed visible hepatic steatosis and ballooning degeneration; 4 with occult hepatitis B, which presented with portal inflammation and infiltration of lymphocytes and were positive for HBcAg and/or HBsAg as revealed by immunohistochemistry; 2 with hepatic amyloidosis, which showed a lot of eosin amyloid deposits reactive with Congo red in liver cells and blood sinus; 2 with hemochromatosis, which showed obvious iron pigment deposition in liver cells; 2 with glycogen storage disease, which showed extensive hyaline degeneration in hepatic cells and was positive for Dpas; 1 with schistosomiasis with schistosome eggs detected microscopically; 1 with toxoplasmosis, and electron microscopy revealed Toxoplasma gondii rhoptry; 1 with Dubin-Johnson syndrome, which showed thick, dark brown pigment particles in liver cells. There were still 6 cases in whom a definite diagnosis could not be achieved after liver biopsy. CONCLUSION: Autoimmune liver diseases are main causes of liver injury of unknown causes, followed by NAFLD. Liver parasite, genetic diseases and metabolic diseases are rare. Liver biopsy should be emphasized in patients with liver injury of unknown reasons. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.