Abstract Background: Epithelial cell transforming sequence 2 (ECT2) and epidermal growth factor receptor (EGFR) have been identified as promising novel therapeutic targets and prognostic markers in different types of cancer. Aim: To evaluate the expression of (ECT2) and (EGFR) in laryngeal squamous cell carcinoma (LSCC) and its prognostic significance. Methods: The expression of ECT2 protein and EGFR was investigated in 15 excisional biopsies of benign vocal cord polyps and 46 cases of LSCC. The association between ECT2 and EGFR expression and clinicopathological characteristics of LSCC was also analyzed. Survival analysis of LSCC patients were also analyzed using Kaplan-Meier survival curves. Results: Up regulation of ECT2 expression was detected in 28 (60.9%) cases of LSCC tissues and that was higher than those of benign laryngeal tissue (P<0.001). Overexpression of ECT2 was related to pT stage (P<0.001), TNM stage (p=0.001) and lymph node metastasis (P= 0.02) in LSCC. Significant difference in EGFR expression was detected between LSCC tissues and benign laryngeal tissue (P<0.001). Overexpression of EGFR was related to pT stage (P< 0.001), TNM stage (P= 0.01) and lymph node metastasis (P=0.006). Moreover survival analyses revealed that high ECT2 and EGFR expression was associated with worse 3-year overall survival (OS) and 3-year disease-free survival (DFS) in (LSCC) patients. Conclusion: Overexpression of ECT2 and EGFR contribute to tumor invasion, progression and poor survival, suggesting that ECT2 and EGFR could be potential prognostic markers for (LSCC) patients.