Aims: This study aimed to investigate the potential impact of tacrolimus (TAC) exposure on clinical outcomes after lung transplantation. Methods: This retrospective observational study enrolled a total of 234 lung transplant recipients. TAC trough levels (C₀) were collected for 3 intervals: 0–3 months, 3–12 months, and 12–24 months. The intra-patient variability (IPV) was calculated using coefficient of variation. Genotyping of CYP3A5*3 (rs776746) was performed. Patients were further divided into groups based on the C₀ cut-off value of 8 ng/mL and IPV cut-off value of 30%. Cox proportional hazards regression models were used to explore the potential impact of C₀ and IPV on outcomes of interests, including donor-specific antibodies (DSA), chronic lung allograft dysfunction (CLAD) and mortality. Results: The influence of CYP3A5*3 polymorphism was only significant for C₀ and IPV during the first 3 months. Low C₀ (< 8 ng/mL) at 3–12 months increased the risk of DSA (hazard ratio [HR] 2.820, 95% confidence interval [CI] 1.093–7.276) and mortality (HR 2.220, 95% CI 1.162–4.243), while High IPV (>=30%) during this period was associated with an increased risk of mortality (HR 2.100, 95% CI 1.120–3.937). Patients with Low C₀/High IPV combination had significantly higher risks for DSA (HR 4.534, 95% CI 1.326–15.507) and survival (HR 4.205, 95% CI 1.739–10.168), surpassing the predictive power provided by C₀ or IPV alone. Conclusion: A combination of Low C₀/High IPV might be considered in categorizing patients towards risk of adverse clinical outcomes following lung transplantation.