BACKGROUND: The health and economic benefits of the annual influenza vaccine are well documented, yet vaccination rates in the United States missed the Healthy People 2020 goal and remain a focus of Healthy People 2030 efforts. By identifying underlying reasons for low annual influenza vaccination, social elements that need targeting may be identified and could guide future interventions or policy development to achieve vaccination goals and improve overall public health. OBJECTIVE: To determine the influence of certain social determinants of health on adherence to annual influenza vaccination in American adults. METHODS: This was a retrospective cohort analysis using data from IBM MarketScan Commercial Claims and Encounters Database and national Medicare 5% sample data from 2013 to 2016. Study eligibility criteria included adults (aged 18 years and older) who were continuously enrolled for 3 influenza seasons between 2013 and 2016. Receipt of the influenza vaccine was counted over 3 consecutive influenza seasons, and select social determinants were extracted from publicly available sources. Patient characteristics, health resource utilization, and selected social determinants of health were included in bivariate and multivariate logistic regression analyses to determine their association with annual influenza vaccination. RESULTS: 6,694,571 adults across employer-sponsored and Medicare coverage groups were analyzed, of which 14.7% of Medicare-enrolled adults and 9.2% of commercially enrolled adults were vaccinated in all 3 seasons. Higher proportions of vaccine adherence (ie, all 3 seasons) were observed among females (9.6% vs 8.7% [commercial], 15.0% vs 14.4% [Medicare]), the immunocompromised (11.8% vs 8.3% [commercial], 15.9% vs 13.6% [Medicare]), rural residents (10.5% vs 9.0% [commercial], 15.4% vs 14.6% [Medicare]; all P < 0.0001), and those enrolled in a high-deductible health plan (10.3%). Multivariable logistic regression models indicated that the odds of vaccine adherence tended to be higher in areas of higher poverty (OR=1.012; 95% CI = 1.01-1.02 [commercial], OR=1.01; 95% CI = 1.01-1.01 [Medicare]) yet lower in areas with higher proportions of Democratic voters (OR=0.998; 95% CI = 0.998-0.998 [commercial], OR = 0.996; 95% CI = 0.996-0.997 [Medicare]). Among commercially insured adults, the odds of vaccine adherence were higher in areas of higher health literacy (OR=1.036; 95% CI = 1.036-1.037), but this effect was not observed among Medicare members. Conversely, the odds of vaccine adherence increased as the proportion of those residing in areas of limited Internet access increased (OR=1.007; 95% CI = 1.004-1.010) among Medicare members only. CONCLUSIONS: Key social determinants of health are important factors of vaccine adherence and can guide policy and intervention efforts toward addressing potential hesitancy. A deeper assessment of other contributing social factors is needed in seasonal influenza and other vaccines to better interpret the vaccine-seeking behaviors of adults. DISCLOSURES: This study received no outside funding. Gatwood, Hagemann, Hohmeier, and Chiu declare vaccine-related grant funding from Merck & Co. and GlaxoSmithKline for vaccine research unrelated to the current study. Ramachandran declares vaccine-related grant funding from Glaxo-SmithKline for research unrelated to the current study. Shuvo and Behal have nothing to disclose. Findings described in this study were presented as a poster and podium at the Academy of Managed Care Pharmacy Nexus 2020 Virtual meeting, October 19-23, 2020.