Objective: To investigate the differences and similarities between drug-induced liver injury (DILI) and autoimmune hepatitis (AIH) in serum biochemical parameters and liver pathology, and to provide some thoughts for clinical diagnosis and differentiation of these two diseases. Methods: A retrospective analysis was performed for the biochemical, immunological, autoantibody, and liver pathological data of 106 DILI patients and 63 AIH patients who were hospitalized, diagnosed, and treated in our hospital from January 2012 to October 2014. The patients' general data, biochemical parameters, immunological data, Ishak score, and qualitative changes in liver tissue were analyzed and compared. The Kruskal-Wallis test was used for comparison of nonparametric data between multiple groups, the Nemenyi test was used for comparison of nonparametric data between any two groups, the Wilcoxon rank sum test was used for comparison of Ishak scores, and the chi-square test was used for comparison of constituent ratio of categorical data. Results: There were significant differences between AIH group and DILI hepatocyte injury group/mixed-type DILI group in the following serum biochemical parameters: alanine aminotransferase (187.2 U/Lvs 1 326.5 U/L and 455.6,P< 0.05), aspartate aminotransferase (172.2 U/L vs 759.5 U/L and 349.5 U/L,P<0.05), alkaline phosphatase (209.3 U/L vs 157.3 U/L and 169.4 U/L,P< 0.05), gamma-glutamyl transferase (254.8 U/L vs 176.5 U/L and 170.5 U/L,P< 0.05), total bilirubin (37.2µmol/L vs 95.8µmol/L and 52.6µmol/L,P< 0.05), serum iron (18.9µmol/L vs 36.2µmol/L and 23.9µmol/L,P< 0.05), serum ferritin (122.5µmol/L vs 410.4µmol/L and 186.5µmol/L,P< 0.05), immunoglobulin G (18.4 g/L vs 12.6 g/L and 12.3 g/L,P< 0.05), and immunoglobulin M (1.8 g/L vs 1.3 g/L and 1.1 g/L,P< 0.05). There were also significant differences between AIH group and DILI hepatocyte injury group/mixed-type DILI group in the Ishak score for interface inflammation (2.2±0.8 vs 1.3±0.7 and 1.3±0.6,P< 0.05), Ishak score for portal inflammation (2.3±0.9 vs 1.5±0.7 and 1.4±0.8,P< 0.05), and fibrosis score (2.8±1.1 vs 1.5±0.7 and 1.3±0.7,P< 0.05). There were significant differences between AIH group and DILI hepatocyte injury group/mixed-type DILI group in the proportion of wax-like deposition (0 vs 29.2% and 34.5%, P <0.05) and proportion of iron deposition (11.1% vs 52.1% and 25.9%,P< 0.05). Conclusion: There are differences in biochemistry, immunology, and liver histology between DILI and AIH patients. AIH patients have more serious interface inflammation and portal inflammation and a higher fibrosis degree compared with DILI patients, while DILI patients have greater proportions of wax-like deposition and iron deposition compared with AIH patients.