Abstract Background: The purpose of this study is to examine the association between statin use and head and neck squamous cell carcinoma (HNSCC) outcomes: overall death, HNSCC-specific death and recurrence. Statins possess anti-cancer properties such as anti-inflammatory and immunomodulatory effects, and have been found to be protective against cancer risk and mortality across various cancer sites. However, little research has been done examining the association between statin use and HNSCC outcomes. Methods: Incident HNSCC patients (n=1,843) were recruited through the University of Michigan Rogel Cancer Center to participate in the University of Michigan Head and Neck Cancer Specialized Program of Research Excellence (SPORE) from 2003-2014. Statin data were collected retrospectively from SPORE participants through medical record review. Participants were identified as being a statin user if they had used a statin at or after diagnosis. Outcome data were also collected through medical record review as well as Social Security Death Master File and LexisNexis. Our analytic cohort included 1,642 SPORE participants who had information on both statin use and HNSCC outcomes. Cox proportional hazard models were used to estimate the association between ever statin use and HNSCC outcomes. The following factors were considered as potential confounders; age, gender, race, comorbidities, smoking status, body mass index (BMI) and education. All estimates presented are from the final multivariable models which included age, comorbidities and BMI as only these variables changed the point estimate by >10%. Results: 35.9% of participants were ever statin users. Overall, we observed a statistically significant inverse association between ever using a statin and both overall death (HR=0.74, 95%CI=0.63-0.88) and HNSCC-specific death (HR=0.79, 95%CI=0.63-0.99). We observed an inverse association with recurrence, although it was not statistically significant (HR=0.85, 95%CI=0.70-1.04). We observed a statistically significant interaction such that the inverse associations for HNSCC-specific death and recurrence were restricted to patients with human papillomavirus (HPV) positive disease (HNSCC-specific death: HPV+ HR=0.43, 95%CI=0.21-0.86; HPV- HR=1.02, 95%CI=0.71-1.47; p-int-0.02; recurrence: HPV+ HR=0.50, 95%CI=0.30-0.86; HPV- HR=1.02, 95%CI=0.74-1.41; p-int-0.02); statins were inversely associated with overall death in both HPV positive and negative patients. Analyses stratified by disease site supported the HPV interaction; the strongest inverse association was observed for oropharyngeal cancers. Conclusion: Our findings from this large, prospective study demonstrate that statin use may be protective for adverse outcomes in HNSCC patients, particularly those with HPV positive disease. If true, these findings could have a meaningful impact on tertiary prevention for this cancer, which currently has unacceptably low survival rates. Citation Format: Kayla R. Getz, Emily Bellile, Katie Zarins, Steven Chinn, Jeremy Taylor, Laura Rozek, Gregory Wolf, Alison Mondul. Statin use and head and neck cancer outcomes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3391.