Abstract Purpose: The COVID-19 pandemic has disrupted many facets of life for rural and urban patients with cancer. Here, we characterize the impact of the pandemic on social and health behaviors of rural and urban cancer patients. Methods: N=1,326 adult cancer patients, who visited HCI in the last 4 years and enrolled in either Total Cancer Care or Precision Exercise Prescription studies, completed a COVID-19 survey. The survey was administered between Aug and Sept 2020 and included questions on demographic and clinical information as well as employment status, health behaviors, and COVID-19 prevention measures. Results: The mean age was 61 (19-92) years, with 54% female, 97% non-Hispanic White, 80% stage I-III, 42% employed full or part-time, 25% living in rural counties, and 85% reporting good to excellent overall health. Cancer patients in rural compared to urban counties were more likely to be older (rural=63 vs. urban=60 years; p=0.01), retired or not employed (rural=63% vs. urban=56%; p=0.04), not have health insurance coverage (rural=4% vs. urban=2%; p=0.01), and have ever smoked (rural=35% vs. urban=24%; p=0.001). However, urban patients reported “somewhat” to “a lot” of change in their daily lives more frequently than rural patients (urban=86% vs. rural=77%; p<0.001), but there were no differences in change in social interaction or feeling lonely between populations. Changes in health behaviors namely exercise habits due to the pandemic were more common in patients residing in urban vs. rural counties (urban=51% vs. rural=39%; p<0.001), with more urban patients either exercising less (urban=23% vs. rural=17%) or more frequently (urban=12% vs. rural=8%); however, there were no significant differences with respect to changes in alcohol consumption between these groups. In terms of prevention measures, urban patients compared to rural patients were more likely to use face masks “fairly” or “very often” (urban=94% vs. rural=83%; p<0.001) and also felt they were more likely to contract a COVID-19 infection (22% vs. 14%; p=0.003), but there were no differences for other risk mitigation behaviors, such as hand sanitizer use. Conclusion: These findings suggest that the first 6 months of the COVID-19 pandemic had disparate effects on cancer patients living in rural and urban counties. Rural patients were more likely to have risk factors associated with poor health outcomes, such as not having health insurance coverage and having a history of smoking. However, urban patients were more likely to experience larger changes in their daily lives and exercise habits. Urban patients were more likely to follow preventive measures (e.g., wearing face masks) and felt they were at a greater risk of contracting the virus. Further research is needed to better characterize the pandemic's short- and long-term effects on cancer patients in rural and urban settings and appropriate interventions. Funding: U01CA206110, R01CA211705. Citation Format: Bailee Daniels, Caroline Himbert, Cassandra A. Hathway, Tengda Lin, Karen Salas, Anjelica Ashworth, Anne C. Kirchhoff, Anna Beck, Cindy Matsen, Courtney Scaife, Cristina Christenson, Douglas Grossman, Howard Colman, Jason P. Hunt, Jennifer Ose, Jonathan Tward, Kevin B. Jones, Michael Deininger, Mikaela Larson, Paul LaStayo, Thomas Varghese, Tracy Onega, Wallace L. Akerley, Frank J. Penedo, Erin M. Siegel, Cornelia M. Ulrich, Shelley S. Tworoger, Anita R. Peoples. Impact of the COVID-19 pandemic on social and health behaviors among rural and urban cancer patients at Huntsman Cancer Institute (HCI) [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr S04-03.