Increasing evidence suggests that the tumor microenvironment plays an important role in tumor progression and oncogenesis. Various proinflammatory mediators contribute to tumor proliferation, neoangiogenesis, invasion, metastasis, and resistance to cancer therapy such as hormonal therapy and chemotherapy. The major causes of death related to head and neck squamous cell carcinoma (HNSCC) include cervical node and distant metastases. Epithelial-mesenchymal transition (EMT) has been identified to play a key role in mediating the tumor invasion and metastasis of carcinomas. Herein, the relationship between proinflammatory mediators and EMT in HNSCC was investigated. Immunohistochemical expression of interleukin-1 β (IL-1β), cyclooxygenase-2 (COX-2), Slug and E-cadherin in relationship to histologic differentiation, clinical stage and nodal status was evaluated in 146 surgical specimens of HNSCC. A correlation was noted between increased expression of IL-1β and nodal status, as well as increased expression of COX-2 and histologic differentiation, clinical stage and nodal status. Increased Slug expression was correlated with histologic differentiation and clinical stage. Decreased E-cadherin expression was correlated with histologic differentiation and nodal status. A significant relationship was observed between IL-1β and COX-2. However, a significant inverse correlation was noted between Slug and E-cadherin. A significant relationship was observed between increased proinflammatory mediator IL-1β/COX-2 expression and increased EMT marker Slug/E-cadherin expression. These results indicate that proinflammatory mediators IL-1β and COX-2 may induce EMT through an increase in Slug and a decrease in E-cadherin. The present findings suggest that various anti-inflammatory agents could be used as an adjuvant treatment modality with anti-cancer chemotherapeutic drugs in HNSCC.