Idiopathic post-transplantation hepatitis (IPTH) is a common histology occurring late after liver transplantation. Its natural history and the effect of treatment have not been determined. This study is a matched case-control study that evaluates predictors, outcome and response to treatment for IPTH. Patients were divided by autoantibodies into high-titre (> or = 1:160) and low-titre (<1:160) groups, so as to evaluate clinicopathological differences between the two groups. IPTH was identified in 42 of 944 recipients (4.4%) with tacrolimus-based immunosuppression. They comprised 10 males and 32 females, having median age 6.0 (0-50) years. IPTH presented at a median duration of 5.2 (0.7-10.8) years after transplantation. Particular risk of IPTH was associated with acute rejection, late-onset acute rejection occurring later than 6 month post-transplant, and autoantibody positivity. IPTH was associated with dependence on steroids and frequent adverse outcomes: retransplantation in five (12%); relapse in four (9.5%); and progression of fibrosis in eight (19%). The high-titre group and low-titre group did not differ in their clinicopathological features, response to treatment or outcome. To prevent the development of IPTH, appropriate adjustment of immunosuppression and close follow-up is necessary for patients who suffer repeated episodes of rejection.