Objectives: Laminin-5 γ2 chain (LN-5 γ2) is an extracellular matrix protein that plays an important role in cell migration and tumor invasion. We evaluated the association of LN-5 γ2 and epidermal growth factor receptor (EGFR) expression in esophageal squamous cell carcinoma (SCC). Methods: LN-5 γ2 and EGFR expression was evaluated in 110 esophageal SCC patients by immunohistochemistry, and was confirmed using esophageal SCC cell lines by Western blot analysis. Results: LN-5 γ2 expression in the invasive front of the tumor was correlated with the depth of invasion (p = 0.0001), lymph node metastasis (p = 0.0011) and pathological stage (p = 0.0001). The strong expression of EGFR was also correlated with lymph node metastasis (p = 0.0456) and the pathological stage (p = 0.0055). In patient survival, LN-5 γ2 positivity and/or strong EGFR expression showed a significantly low survival rate as compared with those with lesser expression of LN-5 γ2 and EGFR. Immunohistochemically, LN-5 γ2 expression was significantly correlated with EGFR expression (p < 0.0001). Western blot analysis also confirmed the correlated expression of LN-5 γ2 and EGFR in SCC cell lines except 2 of the 5 cell lines. Conclusions: This study suggests that coexpression of LN-5 γ2 and EGFR is closely related to the progression and poor prognosis of esophageal SCC.