Objectives: This work was performed to study the pharmacokinetics of tacrolimus in adult liver transplant recipients after optimization of all the known classic factors contributing to inter-patient variability in whole blood tacrolimus levels. Also, to detect if any variability in whole blood tacrolimus levels still exists or this variability is only a function of the classic co-variables so that their optimization will diminish or eliminate it. Methods: Twenty-Six male patients with end-stage liver disease undergoing living donor liver transplantation were selected from the Gastroenterology Department of the International Medical Center, Cairo, Egypt, were enrolled in the study. A patient is initially considered to be a candidate for this study when tacrolimus was indicated as a part of a triple immune suppressive regimen with mycophenolate mofetil and prednisolone. Patients were selected to have non-significant variations in their demographics and pretreatment clinical data. Blood samples were drawn from each patient before the morning dose at specified intervals and the whole blood was assayed for tacrolimus, using Chemiluminescent Microparticle Immunoassay method (CMIA). Six months after liver transplantation, patients were classified into 3 groups based on their tacrolimus trough levels; normalized by its daily dose (C/D ratio), into fast, intermediate and slow metabolizers. Results: The results revealed unpredictable variability in whole blood tacrolimus levels among patients at each sampling time and a marked inter-patient variability in mean whole blood tacrolimus levels among individuals throughout the six months post transplantation period, (P value: <0.0001). Considerable inter-patient variability was also evident in tacrolimus pharmacokinetics. During 1^st month post-transplant, tacrolimus C/D ratio varied from 0.53 to 12.2 (ng/ml*1/mg) and tacrolimus oral clearance (CL/F) varied from 3.4 to 79.4 L/hr. At 3^rd month post-transplant, tacrolimus C/D ratio varied from 0.78 to 8.50 (ng/ml*1/mg) and tacrolimus CL/F varied from 4.9 to 53.2 L/hr. At 6^th month post-transplant, tacrolimus C/D ratio varied from 0.73 to 7.10 (ng/ml*1/mg) and tacrolimus CL/F varied from 5.9 to 56.8 L/hr. The overall mean C/D ratio and oral clearance also showed a great variability among patients with a mean of 2.80±1.89 (CV: 67.5%) and 21.3±12.9 (CV:60.7%), respectively. Conclusion: The variability in whole blood tacrolimus concentrations and tacrolimus pharmacokinetics existed in spite of careful patient selection and optimization of all the classic co-variables known to affect tacrolimus concentrations, suggesting the presence of other unstudied factors; the recently evolving genetic factors might contribute to this variability. It is recommended to still considering therapeutic drug monitoring as an integral part of tacrolimus therapy to control variations in response until the discovery of a model that considers all the expected covariates to predict the response.