Squamous cell carcinoma (SCC) of the head and neck is the sixth most frequent cancer worldwide. The survival rate is among the lowest of the major cancers and has not improved significantly in the past two decades. Extensive local invasion and regional lymph node metastasis are, in large part, responsible for the poor clinical outcome of these tumors. Keratin intermediate filaments are the most abundant cytoskeletal proteins in SCCs and regulate the migration of normal and transformed epithelial cells. Previous studies have shown that expression of the 40-kDa keratin K19 is dysregulated in SCCs arising from oral epithelium. Immunohistochemical experiments demonstrated that, while normal epithelium and dysplastic lesions expressed abundant K19 protein, invasive SCCs exhibited a patchy or negative staining pattern. We subsequently determined that K19 expression was consistently downregulated in seven SCC lines compared with normal epithelium. We therefore wanted to determine if K19 downregulation affected the invasive phenotype of these cells. We found that SCC lines which do not express K19 are significantly more invasive in vitro than those which retain expression of this gene. Stable expression of the K19 cDNA in K19 negative cell lines altered cell morphology and intercellular adhesiveness, and significantly decreased the number of cells able to migrate through a reconstituted basement membrane. Reduced invasiveness was not due to decreased metalloproteinase activity in the K19-expressing clones. We conclude that K19 overexpression in oral SCCs decreases their invasive potential by diminishing migratory capability.