CYP3A5genetic variants are associated with tacrolimus metabolism. Controversy remains on whetherCYP3A4increased [*1B(rs2740574),*1G(rs2242480)] and decreased function [*22 (rs35599367)] genetic variants provide additional information. This study aims to address whether tacrolimus dose-adjusted trough concentrations differ between combined CYP3A (CYP3A5 and CYP3A4) phenotype groups. Significant differences between CYP3A phenotype groups in tacrolimus dose-adjusted trough concentrations were found in the early postoperative period and continued to 6 months post-transplant. In CYP3A5 nonexpressers, carriers of CYP3A4*7Bor *7G variants (Group 3) compared toCYP3A4*1/*1(Group 2) patients were found to have lower tacrolimus dose-adjusted trough concentrations at 2 months. In addition, significant differences were found among CYP3A phenotype groups in the dose at discharge and time to therapeutic range while time in therapeutic range was not significantly different. A combined CYP3A phenotype interpretation may provide more nuanced genotype-guided TAC dosing in heart transplant recipients.