The mechanism of idiosyncratic drug‐induced liver injury (IDILI) remains poorly understood, to a large degree because of the lack of a valid animal model. Recently, we reported an animal model in which treatment of female C57BL/6 mice with amodiaquine (AQ) resulted in mild liver injury with a delayed onset and resolution despite continued treatment. Such adaptation is a common outcome in the IDILI caused by drugs that can cause liver failure. We had hypothesized that most IDILI is immune‐mediated and adaptation represents immune tolerance. In this study we found that AQ treatment of Cbl‐b^−/− and PD‐1^−/− mice, which have impaired immune tolerance, resulted in a slightly greater injury. Cotreatment of C57BL/6 with AQ and anti‐CTLA4 also resulted in a greater increase in ALT than treatment with AQ alone; however, these mice also had an increase in T regulatory (Treg) cells and T helper cells expressing PD‐1 and CTLA4. The increase in these cells implies the induction of immune tolerance, and the alanine aminotransferase (ALT) activity in these mice returned to normal despite continued treatment. Cotreatment of PD‐1^−/− mice with anti‐CTLA4 antibody and AQ resulted in the greatest increase in ALT (200‐300 U/L), and necroinflammatory responses characterized by portal infiltration of lymphocytes with interface hepatitis. The lymphocyte infiltration included T and B cells, and the CD8⁺ T cells produced perforin and granzyme. In addition, the ALT activity in PD‐1^−/− mice cotreated with anti‐CTLA4 antibody and AQ did not return to normal, as it had in other mice. Conclusion: We report here the first animal model of IDILI that is similar to the IDILI that occurs in humans, and it was accomplished by inhibiting immune tolerance. (Hepatology 2015;61:1332–1342)