OBJECTIVE: The aim of this study was to clarify the role of IL-33 in tumor progression. METHODS: Surgical specimens from 81 patients with squamous cell carcinoma of the tongue were studied using immunohistochemistry. Primary tumor sections were analyzed for IL-33 and ST2 expression. To examine the influence of IL-33 on the microenvironment of the tumor, we determined the mast cell density (MCD) and microvessel density of the stroma. RESULTS: Patients with high IL-33 expression had a significantly worse prognosis (p=0.004). IL-33 expression was significantly elevated in patients with local and nodal recurrence (p=0.014 and p=0.019). ST2 expression was also associated with a worse prognosis (p=0.024) and was significantly elevated in patients with nodal recurrence (p=0.004). MCD was associated with worse prognosis (p=0.038) and correlated significantly with IL-33 expression (r=0.626, p<0.001). Micovessels in the stroma were significantly increased in the high IL-33 group (p<0.001). CONCLUSION: These data suggest that the IL-33/ST2 axis contributes to tumor aggressiveness and affects the tumor microenvironment. Immunohistochemical evaluation of IL-33 and ST2 is useful for identifying patients at a high risk for poor prognosis.