This study evaluated the pharmacokinetics and pharmacodynamics of a novel 3-dose regimen of daclizumab in de novo hepatitis C liver transplant recipients. In 30 of 156 recipients receiving daclizumab, mycophenolate mofetil, tacrolimus, and no steroids (Arm 3 of Hep C 3 Liver Study), daclizumab (2, 2, and 1 mg/kg, respectively) was given on days 1, 3, and 8 posttransplant, respectively, with trough, peak (Cmax), and CD25 saturation (CDsat) measured sequentially. Mean daclizumab Cmax was 50.3 μg/mL on day 1, and mean trough levels were 21.8, 25.7, and 9.9 μg/mL on days 3, 8, and 30, respectively. A significant decline in CDsat (mean, 15.7% to 4.7%) was observed on day 1 and was sustained throughout the study (2.8% on day 30). Daclizumab concentration ≥5 μg/mL was the level where most of the effect on CDsat was noticed. Elevated baseline CDsat was observed in African Americans, patients weighing ≤75 kg, and patients <60 years of age. After 365 days, 2 patients had experienced 3 rejections, 10 patients had recurrent hepatitis C, 4 patients died, and 2 grafts were lost. In conclusion, this novel 3-dose regimen is effective in rapidly achieving high therapeutic concentration of daclizumab and a significant decline in CDsat lasting over 30 days. Liver Transpl 12:585–591, 2006. © 2006 AASLD.