Abstract: Objective: To investigate the expression of HPSE and VEGF and its clinical significance in head and neck squamous cell carcinoma (H&NSCC). Methods: The expression of HPSE and VEGF in normal mucosa and 62 specimens of primary tumor and metastatic lymph node lesions of H&NSCC was detected with immunohistochemistry and flow cytometry. Computer-assisted image analysis was used to obtain the results. Results: The expression of HPSE and VEGF in H&NSCC tissues was higher than that in normal mucosa(P<0.01). The expression of HPSE and VEGF in H&NSCC with metastatic lymph node lesions was higher than that in those without metastasis(HPSE: P<0.05, VEGF: P<0.01). No significant difference was found in the expression of HPSE and VEGF between the primary lesions and their metastatic lymph node lesions (P>0.05), but a positive correlation was found between them (HPSE: r=0.9162, P<0.01; VEGF: r=0.9278, P<0.01). The expression of HPSE and VEGF was correlated with the clinical staging (P<0.05). A positive correlation between the expression of HPSE and VEGF (r=0.7602, P<0.01) was identified. There was a negative correlation between HPSE expression and survival(r=-0.647, P<0.01) and between VEGF expression and survival(r=-0.568, P<0.01). Conclusion: Expression of HPSE and VEGF in H&NSCC correlates with clinical staging, metastatic lymph node lesions and prognosis. The high expression of the two genes suggests they play important roles in the occurrence and metastasis of H&NSCC.