Background: Human Papilloma Virus  HPV  related oropharyngeal squamous cell cancer  OPSCC  is distinct from that attributable to tobacco use, ith better prognosis and treatment response. While HPV status doesnx0027;t currently influence treatment decisions, clinical trials are exploring de-intensification strategies for HPV+ OPSCC. While no gold standard tests exist, immunohistochemistry  IHC  for P16, hich is a surrogate marker for HPV and HPV DNA in-situ hybridization  ISH  are commonly used for determining HPV status. Discordance beteen these tests is frequent, and no guidelines exist ith regards to their use. As e advance toards HPV-specific protocols, accurate assessment of HPV status is essential. We evaluated the concordance of HPV P16 and HPV ISH for OPSCC, ith special focus on never-smokers, in ho tumors are likely HPV-related. Methods: Charts of patients ith OPSCC diagnosed beteen 2012 and 2014 ere revieed. Data included age, gender, stage, smoking, primary site, and HPV status. Descriptive statistics ere used to summarize the data. Results: 50 patients ere analyzed. 39 ere male  78 percent  and median age as 61.5 years. Most common primary site as base of tongue  n = 28, 56 percent  folloed by tonsil  n = 19, 38 percent . Most patients had advanced disease: 16 stage III  32 percent , 31 stage IVA  62  percent , 1 stage IVB  2 percent . P16 IHC as performed in 48  96 percent  and ISH in 43  86 percent . Wide spectrum  WS  ISH as utilized in 23  46 percent  and HPV 1618 ISH in 23  46 percent . P16 stained strong and diffuse in 35  70 percent  and eak in 5  10 percent . HPV ISH as positive in 20  40 percent ; 9 WS and 11 HPV 1618. All HPV ISH positive tumors stained for P16  100 percent . Amongst never-smokers  n = 20 , P16 as diffusely positive in 1919 tested  100 percent , hereas HPV ISH as positive in 817  47 percent . Conclusions: Discordance beteen P16 IHC and HPV ISH is high. P16 is more sensitive in never-smokers. We conclude that HPV ISH has lo utility and recommend the utilization of P16 IHC only for diagnostic and prognostic purposes in OPSCC pending availability of improved testing techniques.,J Clin Oncol 34, 2016  suppl; abstr 6065 00:00.0,Head and Neck Cancer