Objective. Protein 4.1N (4.1N) is a member of the Protein 4.1 family that is involved in cellular processes such as cell adhesion, migration and signaling. In this study, we evaluated the expression of 4.1N protein and its potential roles in epithelial ovarian cancer (EOC) tumorigenesis and progression. Methods. 4.1N protein expression was investigated in a total of 280 samples including 74 normal tissues, 35 benign, 30 borderline and 141 malignant epithelial ovarian tumors by immunohistochemistry. Correlation between 4.1N expression levels and clinicopathologic features was statistically analyzed. The expression of 4.1N in EOC cell lines was examined by western blotting. Results. Immunohistochemistry analysis revealed that, although there was no loss of 4.1N expression in normal tissues and benign tumors, absence of Protein 4.1N was significantly more common in EOCs (44.0%) than in borderline tumors (3.3%) (p < 0.001). Furthermore, loss or decreased expression of 4.1N protein expression was correlated with malignant potential of the tumors (14.3% in benign tumors, 56.7% in borderline tumors and 92.9% in malignancy) (p < 0.001). In EOC samples, loss of 4.1N protein was significantly associated with advanced-stage (p = 0.004), ascites (p = 0.009), omental metastasis (p = 0.018), suboptimal debulking (p = 0.024), poorly histological differentiation (p = 0.009), high-grade serous carcinoma (p = 0.001), short progression-free-survival (p = 0.018) and poor chemosensitivity to first-line chemotherapy (p = 0.029). Moreover, western blotting analysis revealed that expression of 4.1N protein Was lost in 4/8 (50%) EOC cell lines. Conclusions. 4.1N protein expression level was significantly decreased during malignant transformation of epithelial ovarian tumors and that loss of 4.1N expression was closely correlated to poorly differentiated and biologically aggressive EOCs. (C) 2013 Elsevier Inc. All rights reserved.