Cholangiocarcinoma (CCA), a slow growing but highly metastatic tumor, is highly prevalent in NortheastThailand. Specific tests that predict prognosis of CCA remain elusive. The present study was designed toinvestigate whether peripheral blood leukocyte (PBL) transcriptional profiles might be of use as a prognostictest in CCA patients. Gene expression profiles of PBLs from 9 CCA and 8 healthy subjects were conducted usingthe Affymetrix HG_U133 Plus 2.0 GeneChip. We indentified informative PBLs gene expression profiles thatcould reliably distinguish CCA patients from healthy subjects. Of these CCA specific genes, 117 genes were upregulated and 60 were down regulated. The molecular and cellular functions predicted for these CCA specificgenes according to the Gene Ontology database indicated differential PBL expression of host immune responseand tumor progression genes (EREG, TGF β1, CXCL2, CXCL3, IL-8, and VEGFA). The expression levels of9 differentially expressed genes were verified in 36 CCA vs 20 healthy subjects. A set of three tumor invasionrelated genes (PLAU, CTSL and SERPINB2) computed as “prognostic index” was found to be an independentand statistically significant predictor for CCA patient survival. The present study shows that CCA PBLs mayserve as disease predictive clinically accessible surrogates for indentifying expressed genes reflective of CCAdisease severity.