Liver transplantation (LT) is the primary treatment for selected patients with hepatocellular carcinoma (HCC). However, HCC-related mortality post-LT remains a significant concern, with up to 10% of cases reported in international series. Identifying risk factors for adverse clinical outcomes is essential. We hypothesized that post-LT HCC-related mortality rates are higher in patients with a high (≥ 42) Comprehensive Complication Index (CCI) calculated at discharge. This study aims to compare post-LT HCC-related mortality rates between two groups of patients with high versus low CCI following LT for HCC. This study included data from seven collaborative European centers. A cohort of 1121 HCC patients transplanted between 2005 and 2019, surviving more than six months post-LT, was analyzed retrospectively. Patients were divided into two groups based on the CCI at discharge: Low-CCI Group (n = 942, 84.0%) and High-CCI Group (n = 179, 16.0%). An inverse probability of treatment weighting (IPTW) approach was applied for analysis. In the post-IPTW cohort, four multivariable logistic regression models with mixed effects identified independent risk factors for HCC-related death, overall death, recurrence, and early recurrence. A CCI score of ≥ 42 emerged as an independent risk factor across all models. Specifically, CCI ≥ 42 was associated with increased odds of HCC-related death (OR = 3.35
P <
0.0001), overall death (OR = 2.63
P <
0.0001), overall recurrence (OR = 2.09
P = 0.001), and early recurrence (OR = 1.88
P = 0.02). A CCI score at discharge should be considered a critical factor for recurrence and HCC-related mortality risk. Incorporating CCI into standard post-LT predictive models may enhance prognostic accuracy for adverse HCC outcomes.