BACKGROUND: Infections are a leading cause of early mortality after liver transplantation (LT). Prior to transplantation, cirrhosis-associated immune dysfunction significantly increases the risk of infection. This study investigated the potential of immune monitoring, with a focus on monocytic HLA-DR (mHLA-DR) expression, as a predictor of post-LT complications. METHODS: We conducted a prospective study on 130 patients awaiting LT at Lyon University Hospital to assess mHLA-DR expression, lymphocyte subsets, and T-cell function before and after LT. Multivariate analysis and K-means longitudinal clustering were performed to explore the relationships between immune trajectories and clinical outcomes. RESULTS: Among the 99 patients who underwent LT, 35.4% experienced infections early post-LT. No difference in outcome was found regarding lymphocyte count or function. Delayed mHLA-DR recovery (Day 7 <
11,000 AB/C) and pre-LT MELD scores >
30 emerged as independent infection risk factors, with ORs of 12.1 [4.4-38.2], p <
0.0001 and 4.9 [1.4-18.4], p = 0.01, respectively. Patients with delayed mHLA-DR restoration also had reduced one-year survival (77.8% versus 98.3%, p = 0.003). K-means clustering revealed three distinct mHLA-DR recovery profiles, with the slowest recovery group showing the poorest outcomes. CONCLUSIONS: Our findings highlight mHLA-DR as an early predictor of post-LT infections. Monitoring post-LT immune function through mHLA-DR expression could guide individualized management strategies to improve outcomes. Trial registration The study was registered in the ClinicalTrials.gov registry: NCT03995537, date: June 20, 2019.