Background: Intrahepatic cholangiocarcinoma (ICC) is associated with a poor prognosisrelated to early recurrence especially in the remnant liver after surgery. ICC exhibits a densedesmoplastic stroma which plays a pivotal role in ICC aggressiveness. Thus, analyzing genederegulation in the stroma of ICC may help to identify new prognosis biomarkers andpromising therapeutic targets. The aim of this study was to evaluate the clinical relevanceof the matrix-remodeling enzyme lysyl oxidase-like 2 (LOXL2) expression in ICC.Material and methods: LOXL2 messenger RNA levels were evaluated in microdissected tumoralstroma (TS) and in nontumoral fibrous tissue by gene expression profiling (testingset, n ¼ 10) obtained from gene expression omnibus database and by quantitative real timepolymerase chain reaction (validating set, n ¼ 6). LOXL2 protein levels were evaluated byimmunohistochemistry on a tissue microarray containing 80 independent patients. Therelationship between LOXL2 expression and survival was assessed by univariate andmultivariate analyses.Results: LOXL2 messenger RNA levels were increased in TS, both in the testing and thevalidating sets (P < 0.01). These results were confirmed at a protein level, with a significantlyhigher LOXL2 immunostaining in TS (P < 0.01). Univariate analysis revealed thatLOXL2 expression was correlated with a poor overall survival and disease-free survival(P < 0.01). Importantly, high expression of LOXL2 was an independent prognostic factor ofworst overall survival (hazard ratio ¼ 5.29, confidence interval [CI] 95% ¼ 1.71-16.3, P < 0.01)and disease-free survival (hazard ratio ¼ 5.55, CI 95% ¼ 2.14-14.37, P < 0.01).Conclusions: Our study provides additional arguments for a role of extracellular matrixremodeling in ICC aggressiveness and identifies LOXL2 as a new prognostic marker and apromising therapeutic target in ICC.