The pervasiveness of influenza among humans and its rapid spread during pandemics create a false sense that all humans are affected equally. In this work, we show that neighborhood-level social determinants were associated with greater burdens of pandemic influenza in 1918 and several other diseases in a major US city. We show that literacy, homeownership, and unemployment were associated with cumulative influenza mortality as well as measures of the speed of transmission using a unique dataset describing the home location and week of death of individuals who died during the influenza pandemic in 1918. Our results suggest that, similar to other infectious diseases, social disparities should be a focus of research and public health response in future pandemics. Social factors have been shown to create differential burden of influenza across different geographic areas. We explored the relationship between potential aggregate-level social determinants and mortality during the 1918 influenza pandemic in Chicago using a historical dataset of 7,971 influenza and pneumonia deaths. Census tract-level social factors, including rates of illiteracy, homeownership, population, and unemployment, were assessed as predictors of pandemic mortality in Chicago. Poisson models fit with generalized estimating equations (GEEs) were used to estimate the association between social factors and the risk of influenza and pneumonia mortality. The Poisson model showed that influenza and pneumonia mortality increased, on average, by 32.2% for every 10% increase in illiteracy rate adjusted for population density, homeownership, unemployment, and age. We also found a significant association between transmissibility and population density, illiteracy, and unemployment but not homeownership. Lastly, analysis of the point locations of reported influenza and pneumonia deaths revealed fine-scale spatiotemporal clustering. This study shows that living in census tracts with higher illiteracy rates increased the risk of influenza and pneumonia mortality during the 1918 influenza pandemic in Chicago. Our observation that disparities in structural determinants of neighborhood-level health lead to disparities in influenza incidence in this pandemic suggests that disparities and their determinants should remain targets of research and control in future pandemics.