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The 1-year results of the Phase III U.S. Multicenter Trial comparing tacrolimus (FK506)- and cyclosporine (CsA)-based immunosuppressive therapy in kidney transplantation revealed a significant reduction in the incidence and severity of acute rejection episodes among patients maintained on tacrolimus. The present report at 5 years of follow-up focuses on the long-term impact of tacrolimus treatment on kidney allograft outcome.The study protocol permitted crossover of patients to the alternate treatment arm under stringent conditions. The effect of crossover on graft survival was analyzed. Cardiovascular risk factors and serious adverse events were also monitored over 5 years.Intent-to-treat analysis revealed equivalent patient and graft survival between treatment arms at 5 years of follow-up (79.1% vs. 81.4%;P =0.472 and 64.3% vs. 61.6%;P =0.558 among tacrolimus and CsA-treated patients, respectively). However, the rate of crossover was significantly higher among patients randomized to receive CsA-based therapy (27.5% vs. 9.3%;P <0.001). The incidence of treatment failure (43.8% vs. 56.3%;P =0.008) was significantly lower among tacrolimus-treated patients. Graft survival was significantly improved in the tacrolimus treatment arm when crossover due to rejection was counted as graft failure (63.8% vs. 53.8%;P =0.014). Tacrolimus therapy was also associated with a significantly reduced requirement for medications to control hypertension and hyperlipidemia. There was a substantial rate of reversal of tacrolimus-associated insulin dependence.Tacrolimus-based therapy resulted in significantly reduced risk of graft failure, without an increase in the incidence of adverse events associated with long-term immunosuppression.