Purpose: Head and neck squamous cell carcinoma (HNSCC) shows persistent invasion that frequently leads to local recurrence and distant lymphatic metastasis. However, molecular mechanisms associated with invasion of HNSCC remain poorly understood. We identified IFNinduced transmembrane protein 1 (IFITM1) as a candidate gene for promoting the invasion of HNSCC by comparing the gene expression profiles between parent and a highly invasive clone. Therefore, we examined the role of IFITM1in the invasion of HNSCC. Experimental Design: IFITM1 expression was examined in HNSCC cell lines and cases by reverse transcription^PCR and immunohistochemistry. IFITM1 overexpressing and knockdown cells were generated, and the invasiveness of these cells was examined by in vitro invasion assay. Gene expression profiling of HNSCC cells overexpressing IFITM1versus control cells was examined by microarray. Results: HNSCC cells expressed IFITM1mRNA at higher levels, whereas normal cells did not. By immunohistochemistry, IFITM1 expression was observed in early invasive HNSCC and invasive HNSCC. Interestingly, IFITM1 was expressed at the invasive front of early invasive HNSCC, and higher expression of IFITM1 was found in invasive HNSCC. In fact, IFITM1 overexpression promoted and IFITM1knockdown suppressed the invasion of HNSCC cells in vitro. Gene expression profiling of HNSCC cells overexpressing IFITM1 versus control cells revealed that several genes, including matrix metalloproteinase, were up-regulated in IFITM1overexpressing cells. Conclusion: Our findings suggest that IFITM1plays an important role for the invasion at the early stage of HNSCC progression and that IFITM1can be a therapeutic target for HNSCC.Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer, with an annual incidence of >500,000 cases worldwide (1). The extent of lymph node metastasis is a major determinant in the prognosis of HNSCC. Like most epithelial cancers, HNSCC develops through the accumulation of multiple genetic and epigenetic alterations in a multistep process (2). Recent molecular studies have advanced our understanding of the disease and provided a rationale to develop novel strategies for early detection, classification, prevention, and treatment. Attempts to identify the genes involved in the metastasis are pivotal for the early prediction of HNSCC behavior. The process of metastasis consists of sequential and selective steps, including proliferation, induction of angiogenesis, detachment, motility, invasion into circulation, aggregation and survival in the circulation, cell arrest in distant capillary beds, and extravasation into organ parenchyma (2). We previously established an HNSCC cell line, MSCC-1, from lymph node metastasis (3). Moreover, we isolated a highly invasive clone MSCC-Inv1 from MSCC-1 cells by using an in vitro invasion assay device (4). Then, we compared the transcriptional profile of parent cells (MSCC-1) and a highly invasive clone (MSCC-Inv1) by microarray analysis to identify g...