Two-hour postdose cyclosporine (C2) monitoring is becoming an accepted method of therapeutic drug monitoring, although it is not known whether C2 monitoring is superior to tacrolimus (FK)-based immunosuppression. The purpose of this trial was to compare the safety, efficacy, and pharmacoeconomics of cyclosporine A (CsA) monitored by C2 levels versus FK monitored by trough levels in de novo liver transplant recipients. After informed consent, 60 de novo liver transplant recipients were randomized in a 1:1 fashion to receive either FK (trough, 6-10 ng/mL) or CsA (C2, 600-1200 ng/mL) and corticosteroids. The 2 groups were similar for gender, race, indication for liver disease, and age. At 1 year, patient survival was similar (93% for FK versus 90% for C2). One patient in the FK arm was retransplanted because of recurrent hepatitis C virus (HCV). Early acute rejection occurred in 27% of FK-treated patients and 23% of CsA-treated recipients [P ϭ not significant (NS)]. Recurrent HCV occurred in 21% of FK-treated patients and 61% of CsA-treated patient (P ϭ 0.04). The incidence of other infections, new onset diabetes mellitus, requirement for antihypertensives, and requirement for cholesterol medications were similar between the groups. Annual calcineurin inhibitor costs were lower in the C2 arm ($5432 Ϯ 2091 for C2 versus $8291 Ϯ 3948 for FK, P ϭ 0.001). Annual pretransplant drug costs ($2292 Ϯ 2331 for C2 versus $2831 Ϯ 2358 for FK, P ϭ NS) and 1-year posttransplant drug costs ($17,214 Ϯ 16,600 for C2 versus $15,151 Ϯ 11,699 for FK, P ϭ NS) were similar. In conclusion, immunosuppression with CsA, monitored by C2 levels, is safe, effective, and economical in liver transplant recipients and provides immunosuppression at least equivalent to that of FK.