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What is known and objective: Tacrolimus (Tac) is an immunosuppressant that is widely used to prevent allograft rejection in patients after liver transplantation. Its metabolism mainly depends on the cytochrome P450 3A5 (CYP3A5), which has genetic polymorphisms. Recently, a Chinese herbal medicine known as Wuzhi Capsule (WZC) was shown to increase Tac blood concentrations by inhibiting the activity of CYP3A in animal studies in rats. To date, it remains unexplored whether WZC can be efficiently used to enhance the blood concentration of Tac in liver transplant patients with different donor‐recipient CYP3A5 genotypes. Methods: A total of 185 liver transplant patients were enrolled and two‐way ANOVA was carried out, then they were divided into four groups according to the combinations of donor‐recipient CYP3A5 phenotypes. WZC was given to patients when the dose of Tac was ≥4 mg, and the dose‐adjusted C0 (C0/D) of Tac measured twice in succession was ≤1 ng/ml/mg. The blood trough concentration of Tac (C0), C0/D, and dose‐ and body weight‐adjusted C0 (C0/D/W) was analysed on days 7 and 14 after liver transplantation. Results: The genotypes of donor and recipient or WZC had significant effects on C0, C0/D and C0/D/W. There were significant differences in the Tac blood concentrations between the groups. The recipient expression (*1)/donor expression (*1) (R+/D+) group had the lowest C0, C0/D and C0/D/W among the four groups. Furthermore, a larger proportion of patients in the CYP3A5 expression groups required Tac dose adjustment to achieve a therapeutic effect and were given Tac with WZC. Notably, the use of WZC significantly increased the blood concentrations of Tac in the CYP3A5 expression groups and greater increases in the C0/D and C0/D/W were significantly associated with higher doses of WZC in the CYP3A5 expression groups. What is more, WZC reduced the hospitalization cost of patients to a certain extent. What is new and conclusion: WZC significantly increased the C0, C0/D and C0/D/W in the CYP3A5 expression groups and reduced the hospitalization expenses of patients to a certain extent. What is more, greater increases in the C0/D and C0/D/W were significantly associated with higher doses of WZC. [ABSTRACT FROM AUTHOR]