Unsatisfying long-term survival of intrahepatic cholangiocarcinoma (ICC) triggers the clinicians searching for molecular markers, such as K-ras mutation, to tailor management strategy. Additionally, emergence of tyrosine kinase inhibitors (TKIs) brings new hope to palliate advanced ICC; whether the efficacy of TKIs is influenced by k-ras mutation is largely unknown. This study was designed to determine the prevalence of k-ras mutation and its clinical significance in ICC, as well as to pave the reference for future application of TKIs.A total of 86 patients with ICC who underwent hepatectomy were retrospectively recruited. K-ras mutation was determined by using laser capture microdissection and direct sequencing method. Association among clinicopathological variables and K-ras mutation was analyzed. Prognostic factors of ICC after hepatectomy also were determined.Nineteen (22%) patients exhibited K-ras mutations. Seventeen had their K-ras mutations occurring at codon 12, and the remaining two occurring at codon 13 and codon 61 in one each. Perineural invasion was exclusively the variable associated with K-ras mutation (odds ratio, 6.9) using logistic regression analysis. Multivariate analysis demonstrated that resection margin, T-status, nodal metastasis, and K-ras mutation were independent prognostic factors. The median survival of ICC patients with K-ras mutation was 5.7 months compared with 19.0 months in those without K-ras mutation (P = 0.002).The prevalence of K-ras mutations in a considerably large cohort of ICC was 22%. K-ras mutation is strongly associated with perineural invasion phenotypically. K-ras mutation is an independent prognostic factor of ICC after hepatectomy.