Skin cancer, including basal cell and squamous cell skin carcinoma, is known to\rbe the most common cancer type. Skin cancer is thought to make up half of all known\rcancers. Over one million non-melanoma skin cancers (NMSC) are reported every year. \rApproximately 300,000 of these cases are squamous cell carcinoma (SCC). It is\restimated that about 2,000 people die from NMSC each year. Of the two skin cancer\rtypes, SCC tends to be the more clinically aggressive and likely to spread and invade,\rtypically by way of blood or lymphatic vessels. Understanding the signaling pathways\rin SCC cells that regulate invasion will be important for developing improved cancer\rtreatments. The signal transducer and activator of transcription 3 (Stat3) protein is a\rcentral regulator of numerous cellular activities, including proliferation, survival, and\rmotility. Stat3 also has enhanced activity in many cancers, including skin SCC. This\rstudy shows that Stat3 regulates several invasive properties in a human skin SCC cell culture model.\rHGF (hepatocyte growth factor)- induced cell schattering was assessed for\rSRB12-p9 cells (p9WT), a human skin SCC cell line, along with SRB12-p9 cells\rengineered to have reduced Stat3 activity. Next, a cell viability-based adhesion assay\rwas performed with these cells. Finally, severe combined immunodeficient (SCID)\rmice were injected subcutaneously with P9WT and S3DN cells and tumors were\rmeasured twice weekly. Extracted tumors were analyzed by immunohistochemistry and Western blotting for expression of the invasion related enzyme, MMP-2 and MMP-9.\rThe suppression of Stat3 activity in S3DN cell lines resulted in reduced motility,\rgreater adhesion, and a less invasive phenotype in SCID mice. Immunohistochemistry and Western blotting indicated higher levels of MMPs in the P9WT cells with\rexpression localization towards the outer perimeter of the tumors. This data suggests\rthat Stat3 plays a role in skin SCC invasion and better understanding of Stat3 function\rcould lead to improved treatment and prevention of the disease.