We have compared the pharmacokinetics and pharmacodynamics of cyclosporine between once-and twice-daily dosing regimens in de novo patients of living-donor liver transplantation (LDLT). A total of 14 patients were enrolled in this study, who had received cyclosporine microemulsion (Neoral) twice a day (BID, n ϭ 5) or once daily in the morning (QD, n ϭ 9) after transplantation. On postoperative day (POD) 6, the QD regimen significantly increased cyclosporine exposure; the blood concentration at 2 hours postdose (C 2 ) and area under the concentration-time curve (AUC) for 4 hours (AUC 0 -4 ), compared with the BID regimen. Moreover, the area under the calcineurin (CaN) activity in peripheral blood mononuclear cells time-curve (AUA) for 12 hours (AUA 0 -12 ) and 24 hours (AUA 0 -24 ) were decreased by approximately 42 and 25% with the QD regimen relative to the BID regimen, respectively. The C 2 level was significantly correlated with the AUC 0 -4 (r 2 ϭ 0.95), which was negatively related to the AUA 0 -12 with a large interindividual variability (r 2 ϭ 0.59). However, a significant correlation was found between the AUA 0 -12 or AUA 0 -24 and CaN activity at trough time points. According to a maximum inhibitory effect attributable to the drug (E max ) model, the mean estimates of E max and the C b value that gives a half-maximal effect (EC 50 ) for CaN inhibition were not significantly different between the 2 groups, respectively. These findings suggest that a once daily morning administration of cyclosporine may improve oral absorption and help to provide an effective CaN inhibition early after LDLT. Furthermore, CaN activity at trough time points would be a single surrogate predictor for the overall CaN activity throughout dosing intervals following cyclosporine administration.