Seventy-two long-surviving liver transplant recipients were evaluated prospectively, including a baseline allograft biopsy for weaning off of immunosuppression. Thirteen were removed from candidacy because of chronic rejection (n= 4), hepatitis (n= 2), patient anxiety (n= 5), or lack of cooperation by the local physician (n= 2). The other 59, aged 12–68 years, had stepwise drug weaning with weekly or biweekly monitoring of liver function tests. Their original diagnoses were PBC (n= 9), HCC (n= 1), Wilson’s disease (n= 4), hepatitides (n= 15), Laennec’s cirrhosis (n= 1), biliary atresia (n= 16), cystic fibrosis (n= 1), hemochromatosis (n= 1), hepatic trauma (n= 1), alpha-1-antitrypsin deficiency (n= 9), and secondary biliary cirrhosis (n= 1). Most of the patients had complications of long-term immunosuppression, of which the most significant were renal dysfunction (n= 8), squamous cell carcinoma (n= 2) or verruca vulgaris of skin (n= 9), osteoporosis and/or arthritis (n= 12), obesity (n= 3), hypertension (n= 11), and opportunistic infections (n= 2). When azathioprine was a third drug, it was stopped first. Otherwise, weaning began with prednisone, using the results of corticotropin stimulation testing as a guide. If adrenal insufficiency was diagnosed, patients reduced to< 5 mg/day prednisone were considered off of steroids. The baseline agents (azathioprine, cyclosporine, or FK506) were then gradually reduced in monthly decrements. Complete weaning was accomplished in 16 patients (27.1%) with 3–19 months drug-free follow-up, is progressing in 28 (47.4%), and failed in 15 (25.4%) without graft losses or demonstrable loss of graft function from the rejections. This and our previous experience with self-weaned and other patients off of immunosuppression indicate that a significant percentage of appropriately selected long-surviving liver recipients can unknowingly achieve drug-free graft acceptance. Such attempts should not be contemplated until 5–10 years posttransplantation and then only with careful case selection, close monitoring, and prompt reinstitution of immunosuppression when necessary.