Advances in immunosuppression and surgical care have improved short term patient and graft survival for liver transplant recipients but left us with different challenges: maintaining allograft function while minimizing the long-term immune and non-immune complications related to immunosuppressive medications. This is arguably most important for children who face a long life span and, consequently, a greater potential to develop significant allograft and other end organ damage. The current proposal addresses this challenge by assessing the effectiveness and safety of immunosuppression withdrawal in a well-defined population of pediatric liver transplant recipients whose inherent immune status may predispose to operational tolerance. This proposal brings together expertise from 4 distinct areas, (1) pediatric transplant hepatology and surgery (2) transplant immunology, (3) transplant histopathology and (4) a data coordinating center with extensive experience in pediatric liver transplantation. This experienced and accomplished research consortium aims, during the U34 planning period, to finalize all facets of a clinical trial protocol and associated translational studies, thereby ensuring rapid and smooth trial initiation in the future. With accomplishment of the specified tasks during the U34 tenure, the goals of the forthcoming clinical trial will be to: (1) Conduct a multi-center randomized controlled trial of immunosuppression withdrawal among children more than 48 months after liver transplantation with normal graft function and histology to determine if immunosuppression withdrawal can be done safely with acceptable rates of withdrawal failure in general and allograft rejection in particular. Withdrawal will be considered successful if patients achieve operational tolerance, defined as normal liver allograft function as assessed by liver tests for at least 12 months in the absence of all immunosuppression. (2): Derive predictive biomarkers of operational tolerance for pediatric liver tx recipients using peripheral blood flow cytometry and transcriptional assessment. The hypothesis is that peripheral blood cell phenotypes and transcriptional profiles will predict operational tolerance and suggest pro-tolerant mechanisms. (3). Determine the relationship between immunologic maturity, as assessed by markers of T cell memory and quantitative assessment of T cell responses to viral pathogens, and biomarker accuracy and stability in predicting the outcome of IS withdrawal. The hypothesis is that pro-tolerant biomarker phenotype will be more common in recipients with a limited compared to an expansive T cell memory repertoire engendered by exposure to environmental pathogens. This trial will suggest diagnostic studies that will identify patients for whom immunosuppression withdrawal is safe, elucidate the relationship between protective immunity and alloresponsiveness, and uncover mechanisms involved in spontaneous operational tolerance for pediatric liver transplant recipients.