Tacrolimus (FK 506), a macrolide compound isolated from a bacterium, is a potent immunosuppressant with activity in solid-organ transplants. Most immunosuppressive regimens for liver transplantation are based on cyclosporine. We conducted an open-label, randomized, multicenter trial to compare the efficacy and safety of tacrolimus-based and cyclosporine-based immunosuppressive regimens for patients receiving a first liver transplant. A total of 478 adults and 51 children (< or = 12 years of age) were randomly assigned at the time of transplantation to receive tacrolimus (n = 263) or cyclosporine (n = 266) and were followed for one year. The primary end points were patient and graft survival at one year. The secondary end points were the incidence of acute rejection, corticosteroid-resistant rejection, and refractory rejection (continued rejection after two courses of corticosteroids and an intervening course of muromonab-CD3). According to Kaplan-Meier analysis, actuarial patient-survival rates at day 360 were 88 percent for both the tacrolimus and cyclosporine groups (P = 0.85; 95 percent confidence interval for the difference, -5.4 to 6.6 percent), and graft-survival rates were 82 percent and 79 percent, respectively (P = 0.55; 95 percent confidence interval for the difference, -4.8 to 9.7 percent). Acute rejection occurred in 154 patients in the tacrolimus group and 173 patients in the cyclosporine group (P < 0.002), corticosteroid-resistant rejection occurred in 43 and 82 patients, respectively (P < 0.001), and refractory rejection occurred in 6 and 32 patients, respectively (P < 0.001). Tacrolimus was associated with a higher incidence of adverse events requiring withdrawal from the study, primarily nephrotoxicity and neurotoxicity; 37 patients in the tacrolimus group and 13 in the cyclosporine group discontinued the study because of adverse events (P < 0.001). After one year, immunosuppressive regimens based on tacrolimus and cyclosporine were comparable in terms of patient and graft survival. Tacrolimus was associated with significantly fewer episodes of acute, corticosteroid-resistant, or refractory rejection, but substantially more adverse events requiring discontinuation of the drug.