Head and neck squamous cell carcinoma (HNSCC) is a devastating disease accounting for 500,000 new cancers cases worldwide each year. Only 50% of patients with HNSCC are cured, largely because the majority of cancers are diagnosed in late stage. This challenge is more pronounced in black patients compared to white patients and economically disadvantaged populations compared to wealthy populations. Better diagnostic tests for HNSCC are needed. CD44, hyaluronic acid (HA) and hyaluronidase (HAase) are related molecules involved in the process of tumorigenesis. They exist in soluble form, are detectable in oral rinses, and are measured by simple and inexpensive ELISA or ELISA-like assays. Our main objective is to evaluate the accuracy of a marker panel comprised of soluble CD44, HA and HAase in distinguishing between patients with invasive HNSCC and controls. To do this we will use a case-control study design and will pursue the following Specific Aims. In Specific Aim 1 we determine whether solCD44, HA and HAase levels in oral rinses distinguish between patients with newly diagnosed, invasive HNSCC and high-risk controls with favorable sensitivity and specificity. In Specific Aim 2 we assess short-term variability of solCD44, HA, and HAase levels in oral rinses from control and HNSCC patients. Our long-term goal is to design and perform a definitive screening trial with the outcomes of early detection and most definitively, survival. This project is relevant to the needs of the health care community because it provides the first step towards our long-term goal, and includes the populations most in need of improved detection, namely minorities and the economically disadvantaged.