This study investigated the effect of recipient and donor genetic variability on dose‐adjusted steady‐state tacrolimus concentrations (C ss) and clinical outcomes 3 and 6 months after liver transplant. Twenty‐nine recipients and matched donor blood samples were genotyped for 27 single nucleotide polymorphisms including CYP3A5*3 (rs776746), ABCB1 haplotype and immune genes. Associations between genetic variability and clinical parameters and C ss and the occurrence of rejection and nephrotoxicity were analysed by multivariate and multinomial logistic regression modelling and Jonckheere–Terpstra tests examined the impact of combined donor/recipient CYP3A5 expression on C ss. At 3 months post‐transplant modelling revealed an association between tacrolimus C ss and recipient CASP1 rs580523 genotype ( P = 0.005), accounting for 52% C ss variance. Jonckheere–Terpstra tests revealed that as combined donor/recipient CYP3A5 expression increased, C ss decreased ( P = 0.010 [3 months], 0.018 [6 months]). As this is the first report of CASP1 genetic variability influencing tacrolimus C ss, further validation in larger cohorts is required.