Twelve consecutive liver transplant recipients with stable allograft function and cyclosporine nephrotoxicity were subjected to cyclosporine withdrawal in an attempt to halt and possibly reverse renal damage. Only patients who met the following criteria were included: (a) triple immunosuppression with cyclosporine, azathioprine and prednisone; (b) stable graft function for at least 1 yr without rejection; and (c) serum creatinine greater than 2.1 mg/dl or renal clearance less than 35 ml/min. Cyclosporine was reduced by 50 mg every 3 wk until discontinuation, prednisone was temporarily increased from 10 to 20 mg/day and azathioprine was maintained at 2 mg/kg/day. Sustained improvement in kidney function in the 12 patients was minimal, with the mean serum creatinine level decreasing from 2.5 ± 0.5 mg/dl (mean ± S.D.) at study entry to 2.4 ± 1.2 mg/dl after a mean follow-up of 18 ± 6 mo. In six patients, histologically confirmed cellular rejection developed after a mean of 5 ± 6 mo from the time that cyclosporine withdrawal was begun. Two of six patients with rejection responded to bolus steroid therapy and are in stable condition at this writing with low-dose cyclosporine (2.8 and 3.2 mg/kg/day). Two patients initially responded to bolus steroids but later exhibited ductopenic rejection; one responded to treatment with FK 506 and the other died of sepsis. The two remaining patients were steroid unresponsive. One responded to treatment with OKT3 and is now stable on low-dose cyclosporine (2.3 mg/kg/day), but in the other ductopenic rejection developed and the patient died of sepsis during rescue therapy with FK 506. By comparison, in none of 12 matched control patients did rejection develop during a similar follow-up period. We conclude that cyclosporine withdrawal for nephrotoxicity in liver transplant recipients does not result in sustained improvement in kidney function and causes a high incidence of cellular rejection, which can progress to ductopenic rejection or death from infection. (HEPATOLOGY 1994;19:925–932.)