As outcomes from liver transplantation have improved, attention has focused on long-term outcomes: patient and graft survival is affected by many factors, including the consequences of both overimmunosuppression (eg, renal failure and cancer) and underimmunosuppression (eg, rejection). The use of protocol (rather than event-driven) biopsies of the liver allograft, except for those grafted for HCV infection, has been largely abandoned. The aim of this study was to determine if protocol biopsies can improve the management of liver allograft recipients. A retrospective analysis of liver allograft recipients who had undergone protocol liver biopsies between 2000 and 2006 was performed. One hundred seventy-eight patients with normal liver tests (alcoholic liver disease, 49; autoimmune hepatitis, 20; and primary biliary cirrhosis, 107) who had undergone 235 protocol biopsies were identified. No significant complication from the biopsy was recorded. Liver histology was reported as normal or nearly normal in only 57 (24%). Chronic hepatitis (not obviously related to disease recurrence) was present in 78 (33%). Interpreted in the light of the calculated creatinine clearance, the biopsy findings indicated that overall immunosuppression (IMS) should be maintained or increased with standard calcineurin inhibitor (CNI)-based IMS in 25% of cases, that overall IMS should be reduced in 15% of cases, and that overall IMS should be maintained or increased by the substitution of non-nephrotoxic agents for CNIs in 9% of cases. The histological findings led to a documented change in IMS in 76 (32%) (increased IMS, 11; decreased IMS, 58; and switch from CNI, 7). In conclusion, protocol liver biopsy provides important histological information about graft function that is not available from standard liver tests and safely allows modification of IMS to ensure that long-term side effects of drug therapy (eg, renal failure) are minimized while graft function is sustained. Liver Transpl 15:931-938, 2009. (c) 2009 AASLD.