In a cohort of 298 de-novo renal recipients treated with a standard tacrolimus loading dose of 0.2 mg/kg, the combined effects of the CYP3A5*1, POR*28, and CYP3A4*22 genotypes on early tacrolimus exposure (C0), dose requirements, and achievement of the therapeutic target, C0, were examined. The incidence of clinical events (e.g. acute rejection, diabetes mellitus) was compared between genotypes.Fast metabolizers (CYP3A5*1/POR*28T carriers) had two-fold to three-fold higher tacrolimus dose requirements compared with slow metabolizers (CYP3A5*3/*3/CYP3A4*22 carriers) and needed significantly more time to achieve the target tacrolimus C0 of a minimum 10 ng/ml (3.3±1.7 vs. 1.34±0.75 days; P<0.0001). No differences in acute rejection incidence and time to first rejection were observed. Slow metabolizers more frequently had tacrolimus C0 above the target range early after transplantation (70 vs. 13% on day 3); however, this did not translate into a higher incidence of post-transplantation diabetes mellitus or graft dysfunction. Multivariate analyses identified the CYP3A5*1/POR*28/CYP3A4*22 genotype combination as the single strongest determinant of tacrolimus dose requirements throughout the first year, explaining between 24-40% of its variability, whereas recipient age, hematocrit, and delayed graft function were additional nongenetic determinants of tacrolimus dose.Combining the CYP3A5*1, POR*28 and CYP3A4*22 genotypes allows partial differentiation of early tacrolimus dose requirements and the time to reach therapeutic target concentrations after transplantation, but without obvious clinical implications. Larger prospective studies need to address the clinical relevance of early combined genotype-based tacrolimus dosing in de-novo renal recipients.