Calcineurin inhibitors (CNI) are an important component of most immunosuppressive protocols utilized in renal transplantation. Both CNI available (cyclosporine and tacrolimus) have been used for many years. Studies comparing the efficacy of these two agents in terms of long-term graft or patient survival have thus far failed to show an advantage for either agent. This failure to show a difference could possibly be due to underpowering of clinical trials. The authors used the SRTR database to analyze 5-yr graft survival of the microemulsion formulation of cyclosporine (Neoral) as compared with tacrolimus. To minimize the donor variability and bias, a paired kidney analysis was used. Deceased donors from the years 1995-2002 were analyzed from the SRTR database. All paired kidneys during this period, where one kidney was allocated to a patient receiving initial Neoral therapy and its mate allocated to a patient receiving initial tacrolimus therapy were evaluated. Multivariate and univariate analysis were performed. Univariate analysis demonstrated equivalent graft survival for Neoral compared with tacrolimus (66.9% versus 65.9%, respectively). Multivariate analysis could not demonstrate a difference in risk for 5-yr patient survival or graft loss. Renal function was superior for tacrolimus at all time points, whereas the slope of 1/Cr over time did not differ for the two agents. In this paired kidney analysis, no difference in 5-yr renal allograft survival could be found between the two agents. Renal function was superior in the patients receiving initial tacrolimus therapy; however, slope of 1/Cr did not differ between the agents.