The interaction of CD40 with CD154 is a pivotal trigger of immune cascade-inducing acute liver failure, however its clinical significance has not been well studied. The present study aimed to investigate the clinical implications of serum-soluble CD154 (sCD154) levels and the expression of CD40 on monocytes in patients with fulminant hepatic failure (FHF). The results showed that serum sCD154 levels and CD40 expression on monocytes were significantly higher in FHF patients than in acute hepatitis (AH) patients and healthy controls, and were also significantly higher in FHF patients who died, compared with those who survived. We conclude that high serum levels of sCD154 may be linked to fatal outcome in patients with severe liver injury and may be a valuable prognostic marker for survival in patients with FHF.