The development of sensitive and specific diagnostic assays for the early detection of Head and Neck Cancer is still an unmet medical need. Most assays being developed rely on a neoplastic cell biomarker often present in only a proportion of neoplastic cells and/or a subset of patients with Head and Neck Squamous Cell carcinoma (HNSCC). As such, the intrinsic heterogeneity of the neoplastic cell within a single patient and across patients de facto limits the sensitivity of these assays. To overcome this problem, we propose to monitor HNSCC presence in the oral rinse using RNA aptamers that recognize tumor-infiltrating myeloid cells. These cells infiltrate the lesion in high numbers and early during tumorigenesis, participate in tumor initiation and progression, and predict recurrence in HNSCC. Additionally, these cells are quickly renewed in the tumor microenvironment and release their content in the tumor microenvironment and nearby fluid. We identified four RNA aptamers that recognize myeloid derived suppressor cells and macrophages in the HNSCC tumor but not the myeloid counterparts in the blood or healthy tissues in all patients evaluated. Additionally, our feasibility and proof of principle experiments indicate that these aptamers might discriminate oral rinses of patients with head and neck cancers from those of healthy donors. We propose to test the hypothesis that MDSC-specific aptamers used in linear surface plasmon resonance (LSPR) experiments can detect HNSCC from the oral rinse with high sensitivity and specificity. We will first optimize the assay using samples already banked in our institution. Then, we will perform a prospective clinical study in which we will test oral rinses from 150 patients with biopsy-proven HNSCC (all stage, all sites) and 150 age-matched healthy donors. In particular, we will compare side-by-side the sensitivity and specificity of LSPR assays using as ligand either our MDSC specific aptamers or an antibody against CD44, a marker strongly associated with HNSCC that is being developed for HNSCC diagnosis from the oral rinse with promising results. In summary, we propose a novel approach for the early diagnosis of HNSCC, a disease often diagnosed only in advanced stages when the prognosis is poor, and the treatment morbidity is high. Should our hypothesis be true, we anticipate that assays based on the presence of MDSC may aid in detecting this malignancy at earlier stages when treatments are most effective and less invasive.