Posttransplant de novo autoimmune hepatitis (d-AIH) is increasingly described as a long-term complication after pediatric liver transplantation (LT). d-AIH is characterized by graft dysfunction, the development of autoimmune antibodies and histologic evidence of hepatitis in liver transplant recipients without previous history of autoimmune liver disease. This study is a matched case-control, univariate analysis aimed at identifying risk factors for the development of d-AIH and evaluating response to treatment. From 1984 to 2003, 619 children received 788 LTs at a single center. Forty-one patients developed d-AIH and were matched with controls for year of LT, age at time of LT and diagnosis. The following variables were insignificant in the development of d-AIH: age, gender, race, initial diagnosis, ischemia time, graft type, Epstein-Barr virus and cytomegalovirus status, HLA typing and primary immunosuppression. Compared to controls, d-AIH patients were less likely to be on monotherapy immunosuppression or weaned off prednisone at the time of diagnosis. The d-AIH group relative to the controls had statistically significant greater numbers of rejection episodes. d-AIH was treated with prednisone and/or MMF in 39 of 41 patients and lead to significant improvements in liver function tests. Thirty-nine patients are alive at a mean of 4.0 years follow-up after diagnosis. Three have required retransplantation.