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CD40L and its soluble form (sCD40L) are proteins of the tumor necrosis factor superfamily (TNFSF) that exhibit prothrombotic and proinflammatory properties when binding to CD40, which is a cell surface receptor of the tumor necrosis factor receptor superfamily (TNFRSF). High circulating levels of sCD40L have been associated with poor prognosis in patients with hepatocellular carcinoma (HCC). However, it is unknown whether there is an association between circulating sCD40L levels and survival in patients with HCC underwent to liver transplantation (LT), and this was the objective of that study.Serum sCD40L levels were measured in a total of 139 patients before LT (124 survivors at 1 year of LT and 15 non-survivors). The end-point study was 1 year survival after liver LT.We found that 1-year non-surviving patients showed higher serum sCD40L levels than survivor patients (p = 0.02). We found in logistic regression analysis that serum sCD40L levels higher than 321 pg/mL (Odds Ratio = 6.86; 95% confidence interval = 2.06–22.76; p = 0.002) and age of LT deceased donor were associated with death at 1 year.The new finding of our study was that high serum sCD40L levels previously to LT in patients with HCC are associated with higher mortality at one year.There are higher serum levels of sCD40L previously to LT in patients with HCC in 1-year non-survivor than in survivors.There is an association between serum levels of sCD40L previously to LT in patients with HCC and survival.Serum levels of sCD40L previously to LT in patients with HCC could be used as biomarker of survival.