BACKGROUND: To investigate the potential role of laminin γ2 and its correlation with prognosis in patients with extrahepatic cholangiocarcinoma (CCA). MATERIALS AND METHODS: Laminin γ2 expression was evaluated by immunohistochemistry in 72 extrahepatic CCA patients after surgical resection. Knockdown of laminin γ2 was achieved via small interfering RNA transfection in the extrahepatic CCA cell line QBC939. RESULTS: Thirty-six of 72 extrahepatic CCAs (50%) stained positive for laminin γ2 in two types of patterns: stromal staining (28/72, 39%) and cytoplasmic staining (24/72, 33%). All 16 paracancerous tissue samples showed negative staining. Both stromal and cytoplasmic laminin γ2 expressions correlated with lymph node metastasis. Kaplan-Meier analysis showed that aberrant expression of laminin γ2 correlated with poor overall survival and early recurrence. Cox regression analysis further demonstrated that laminin γ2 expression was a significant independent predictor of poor overall survival and early recurrence. Immunofluorescence staining revealed cytoplasmic expression of laminin γ2 in QBC939 cells. Knockdown of laminin γ2 significantly reduced QBC939 cell invasion and migration. CONCLUSIONS: Aberrant expression of laminin γ2 correlates with poor prognosis and promotes invasion in extrahepatic CCA.