The protease inhibitor SerpinB3 has been recently identified as a critical modulator of the stem-like subset in CCA [29], and in the present study, while confirming the prognostic role of this biomarker at the tumoral tissue level in a larger series of patients with iCCA and eCCA, we uncovered, for the first time, the prognostic roles of free SerpinB3/4 and SerpinB3/4–IgM in the sera of patients with cholangiocarcinoma after diagnosis. The gene discussed is SERPINB3; the disease is cholangiocarcinoma.