Patients with renal failure after liver transplantation have a particularly poor prognosis. Therefore, in the setting of end-stage renal disease requiring dialysis or severe renal insufficiency that will not improve after liver replacement, combined liver-kidney transplantation (LKT) is the preferred approach. We have adopted a policy of LKT in patients with end-stage liver disease and renal insufficiency undergoing dialysis or with a creatinine clearance less than 35 mL/min and evidence of chronic renal dysfunction. Since 1991, we have performed 208 orthotopic liver transplantations. Fourteen patients (8%) have undergone combined LKT, including 6 patients undergoing hemodialysis. Cytotoxic cross-matches (modified Amos technique and antihuman globulin method) were performed on 13 of 14 patients and were positive in 3 patients. Two patients died less than 4 months after LKT and 12 patients are alive and well. Graft survival censored for patient death was 100% for liver allografts and 93% for renal allografts, with a mean follow-up of 39 ± 24 months. The most recent serum creatinine level in the patients with the 11 functioning grafts was 1.1 ± 0.6 mg/dL. Biopsy-proven acute rejection occurred in 50% of simultaneous liver allografts. By contrast, only a single episode (6%) of renal allograft dysfunction was attributable to acute rejection. All rejection episodes occurred in the first 90 days after transplantation and were steroid sensitive. Three of 14 combined procedures were performed in the setting of a positive cytotoxic cross-match. In 2 recent patients, the results were confirmed by positive cross-matches to the donor's T and B cells by flow cytometry. Flow cytometric cross-matches reverted to negative 1 hour after liver transplantation and several hours before the administration of antithymocyte globulin. The cross-matches remained negative on postoperative days 1 and 7. Presently, all 3 patients with a positive cross-match enjoy normal hepatic and renal function at 631, 706, and 2275 days follow-up. Renal scans were performed in 4 LKT recipients not previously undergoing hemodialysis and indicated varying and unpredictable degrees of function in the native and transplanted kidneys. In conclusion, combined LKT can be performed safely and is associated with a low rate of acute rejection, even in the setting of a positive cross-match. Predicting which patients with renal insufficiency will benefit from LKT remains challenging; however, these results suggest that LKT should be encouraged in patients with evidence of irreversible renal insufficiency who require liver transplantation.