BackgroundTacrolimus (TAC) exhibits high pharmacokinetic variability post-liver transplantation (LT). Traditional models overlook the metabolic chimerism between recipient (intestinal) and donor (hepatic) genotypes. We aimed to evaluate a combined donor–recipient CYP3A functional allele count predicting TAC exposure.MethodsThis retrospective study analyzed 1,350 TAC trough measurements from 99 LT recipients. CYP3A4 and CYP3A5 functional alleles were summed into a combined pair-level framework (0–8 alleles). The primary outcome was the log-transformed concentration-to-dose ratio (log-CDR). Linear mixed-effects models (LMM) accounted for repeated measurements, adjusting for clinical and pharmacological covariates.ResultsThe combined CYP3A functional allele count was the strongest genetic predictor of TAC exposure. Using the most prevalent group (4 alleles) as reference in multivariable LMMs, dose-normalized exposure significantly decreased by 43% and 48% in pairs with 5 and 6 functional alleles, respectively (p < 0.001). This gene-dose relationship remained stable across ICU, ward, and outpatient phases. The combined metric captured 4.2% of baseline variance (marginal R2 = 0.042), indicating that most TAC exposure variability is driven by non-genetic clinical factors. Nevertheless, this approach doubled the explanatory power achieved with recipient genotype alone and remained an independent predictor after adjustment for major time-varying clinical confounders.ConclusionThe combined donor–recipient CYP3A functional allele count provides a biologically coherent, temporally stable metric of TAC metabolism. Outperforming single-genome models, it offers a stratification tool to guide early post-operative initial dose strategies.