Background The prevalence of eczema has increased with industrialization. Industrial practices generate ambient air pollution, including fine particulate matter of diameter ≤ 2.5μm (PM2.5). Studies investigating the relationship between PM2.5 and eczema in the US are scarce. The objective of this study was to determine the risk of eczema with PM2.5 exposure in a diverse national cohort of American adults. Methods In this cross-sectional study, eczema cases in the All of Us Research Program were linked via three-digit zip code to average annual PM2.5 concentrations from the Center for Air, Climate, and Energy Solutions. Eczema cases and controls were compared using Pearson’s χ2 test for categorical variables and one-way analysis of variance for continuous variables. The relationship between PM2.5 and eczema was assessed via logistic regression adjusting for demographic factors, smoking, and atopic comorbidities. Results Individuals with eczema (n = 12,695) lived in areas with significan