Higher mortality following SARS-CoV-2 infection in rural versus urban dwellers persists for two years post-infection.

Previous studies demonstrated higher short-term mortality among rural compared with urban residents infected with SARS-CoV-2. However, whether this difference persists remains uncertain. This retrospective cohort study analyzed two-year post-COVID-19 mortality by rurality using the National Clinical Cohort Collaborative COVID-19 Enclave, a United States-based longitudinal electronic health record repository. We analyzed mortality among patients infected with SARS-CoV-2 between April 2020 and December 2022, with follow-up until December 2024. Patients were categorized into urban, urban-adjacent rural (UAR), and nonurban-adjacent rural (NAR) groups based on residential ZIP Code. Mortality differences were assessed using Kaplan-Meier analysis and weighted multivariable Cox regression, with weights derived from demographic factors and models adjusted for background clinical risk and social vulnerability. Among 3,082,978 SARS-CoV-2-infected patients, we found a significant association between rurality and increased two-year all-cause mortality post-infection. Adjusted hazards for two-year mortality for UAR and NAR were 1.19 (95% CI 1.18-1.21) and 1.26 (1.22-1.29). A reference cohort of 4,153,216 COVID-19-negative patients showed a modest yet consistent rural mortality penalty, with a similar relative hazard across cohorts, an observed rurality-COVID-19 interaction, and a greater absolute number of deaths following SARS-CoV-2 infection. Our findings emphasize ongoing rural mortality disparities and the importance of public health efforts in rural communities.