Clinical outcomes, dose changes, and dose-equalized tacrolimus concentrations were examined sequentially in 129 liver transplantation (LT) recipients after successful conversion to once daily modified-release tacrolimus either early (within 1 month) or late (>1 month) after LT. The data were compared with data for a group of 60 patients maintained on twice daily conventional-release tacrolimus. Formulation- and time-dependent changes in dose requirements for once and twice daily tacrolimus differed after transplantation. A 1.7-fold initial increase in the median daily dose was required to achieve target tacrolimus concentrations in the early-conversion cohort (P = 0.006), whereas a 1.25-fold increase was required for those converted later (P = 0.013 and P < 0.001 for the difference). In the subsequent 2 months, the median daily dose fell by 20% in the early-conversion cohort, remained stable for the late-conversion cohort, but rose by 33% with conventional therapy. Lower median dose-equalized concentrations persisted for up to 3 months after the conversion to modified-release therapy. Sex, ethnicity, and the underlying liver disease did not significantly affect these variables. The frequency of treated biopsy-proven acute rejection episodes fell approximately 4-fold after the conversion to modified-release tacrolimus, most notably in the late-conversion cohort, which experienced a high incidence of rejection before conversion. Posttransplant increases in serum creatinine concentrations were smaller after the introduction of modified-release tacrolimus in the late-conversion group (0.7 versus 4 mg/mL for twice daily tacrolimus over 6 months). Reduced interpatient variability in tacrolimus concentrations was evident in the early-conversion cohort versus the twice daily cohort. A decline in intrapatient variability accompanied the reduction in acute rejection in the late-conversion cohort. Our data highlight potential benefits for the rejection rate and renal function on conversion to once daily modified-release tacrolimus late after LT. Liver Transpl 21:29-37, 2015. © 2014 AASLD.