Background: Seroprevalence studies provide an accurate measure of SARS-CoV-2 spread and the presence of asymptomatic cases. They also provide information on the uneven impact of the pandemic, pointing out vulnerable groups to prioritize who is particularly relevant in unequal societies. Here, we estimate the prevalence of SARS-CoV-2 antibodies in three urban centers of Chile and model its spatial risk distribution. Methods :We conducted a population-based serosurvey in Santiago, Talca, and Coquimbo–La Serena (2,493 individuals) and explored the association between positive results and socio-economic and health-related variables by logistic regression for complex surveys. Using an Empirical Bayesian Kriging model, we evaluated the infection risk distribution using individual, household, and census information and compared these results with official records. Findings: Seroprevalence was 10·4% (95%CI 7·8-13·7%), ranging from 2% (Talca) to 11% (Santiago), almost three times the number officially reported. Approximately 36% of these were asymptomatic, reaching 82% below 15 years old. Seroprevalence was associated with the city of residence, previous COVID-19 diagnosis, contact with confirmed cases (especially at household), and foreign nationality. The spatial model accurately interpolated the distribution of disease risk within the cities finding significant differences in the predicted probabilities of SARS-CoV-2 infection by census zone (IQR 2·5%-15·0%), related to population density and education.Interpretation: Our results underscore the transmission heterogeneity of SARS-CoV-2 within and across three urban centers of Chile. Socio-economic factors and the outcomes of this seroprevalence study enable us to identify priority areas for intervention. Our methodological approach and results can help guide the design of interdisciplinary strategies for urban contexts, not only for SARS-CoV-2 but also for other communicable diseases. Funding Information: Chilean National Research Agency, ANID-COVID-19-0589Declaration of Interests: None declared.Ethics Approval Statement: The Ethics Committees of the Universities el Desarrollo and Talca and the Faculty of Medicine of the Universidad Catolica del Norte (Numbers 2020-54, 34-2020, and 21 2020, respectively) approved the study protocols. Depending on age, the participants provided a signed consent to participate in the study; children participated with their assent and parental consent.