Abstract Background: Precision medicine is rapidly becoming incorporated into the management of head and neck cancers. Institutional precision tumor boards are emerging, mostly in frameworks that are not specific to head and neck cancers, and are focused on recurrent and metastatic (R/M) disease. There are significant benefits to a subspecialized focus on head and neck cancers without restricting enrollment to R/M cases. Herein, we discuss the establishment of a unique, upstream head and neck precision oncology program. Methods: We have established a head and neck precision oncology model that is run by head and neck surgeons and translational scientists, in combination with colleagues from radiation oncology, medical oncology, genetics, and ethics. Inclusion criteria stipulate adult patients with biopsy-proven malignancy of the head and neck (newly diagnosed or previously treated, including all sites, stages and histologies) who have pathologic samples available for analysis (fresh frozen or paraffin embedded). Results: We have begun enrolling patients prospectively (n=47 to date; 39 primary tumors and 8 R/M tumors). A custom Illumina 250 gene sequencing panel is utilized for targeted sequencing compared to matched blood. At the time of subject enrollment, we have incorporated a novel informed consent process involving ethicists and genetics counselors, with prospective collection to validate our informed consent process, discussion of disclosure of incidental findings, and clarifying patient expectations. Sequencing data are then presented formally at our head and neck precision oncology tumor board. Discussion: A primary benefit of a head and neck precision oncology tumor board is the integration of multidisciplinary expertise both from a clinical and cancer biology perspective. Our model of counseling, in which we employ a flexible default model of information disclosure, provides unique and valuable prospective information on patient expectations and understanding in disclosure of genetic results, clinical translation, and enrollment in targeted therapy trials. Unique to this model is a focus on enrolling patients up-front, at their initial presentation to our institution. This platform allows for early identification of potential targetable genetic aberrations (in adjuvant and neoadjuvant settings), and allows for evaluation of tumor genomic evolution/mutational selection if the patient develops R/M disease (which may allow for more specific targeted therapy to the mutation that appears to be driving the aggressive tumor biology). Citation Format: Andrew Birkeland, Aditi Kulkarni, Collin Brummel, Susan Foltin, Mark Prince, Carol Bradford, Andrew Shuman, J. Chad Brenner. Establishment of an upstream head and neck precision oncology tumor board [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 19.