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Importance Limited information on the transmission and dynamics of SARS-CoV-2 at the city scale is available. Objective To describe the local spread of SARS-CoV-2 in Valencia, Spain. Design, Setting, and Participants This single-center epidemiological cohort study of patients with SARS-CoV-2 was performed at University General Hospital in Valencia (population in the hospital catchment area, 364 000), a tertiary hospital. The study included all consecutive patients with COVID-19 isolated at home from the start of the COVID-19 pandemic on February 19 until August 31, 2020. Exposures Cases of SARS-CoV-2 infection confirmed by the presence of IgM antibodies or a positive polymerase chain reaction test result on a nasopharyngeal swab were included. Cases in which patients with negative laboratory results met diagnostic and clinical criteria were also included. Main Outcomes and Measures The primary outcome was the characterization of dissemination patterns and connections among the 20 neighborhoods of Valencia during the outbreak. To recreate the transmission network, the inbound and outbound connections were studied for each region, and the relative risk of infection was estimated. Results In total, 2646 patients were included in the analysis. The mean (SD) age was 45.3 (22.5) years; 1203 (46%) were male and 1442 (54%) were female (data were missing for 1); and the overall mortality was 3.7%. The incidence of SARS-CoV-2 cases was higher in neighborhoods with higher household income (β2 [for mean income per household] = 0.197; 95% CI, 0.057-0.351) and greater population density (β1 [inhabitants per km2] = 0.228; 95% CI, 0.085-0.387). Correlations with meteorological variables were not statistically significant. Neighborhood 3, where the hospital and testing facility were located, had the most outbound connections (14). A large residential complex close to the city (neighborhood 20) had the fewest connections (0 outbound and 2 inbound). Five geographically unconnected neighborhoods were of strategic importance in disrupting the transmission network. Conclusions and Relevance This study of local dissemination of SARS-COV-2 revealed nonevident transmission patterns between geographically unconnected areas. The results suggest that tailor-made containment measures could reduce transmission and that hospitals, including testing facilities, play a crucial role in disease transmission. Consequently, the local dynamics of SARS-CoV-2 spread might inform the strategic lockdown of specific neighborhoods to stop the contagion and avoid a citywide lockdown., This study was supported by the Innovation, Universities, Science and Digital Society Council through the Valencia Innovation Agency (AVI); grant 851255 from the European Research Council under the European Union’s Horizon 2020 research and innovation program (Dr Zanin); grant MDM-2017-0711 from the Spanish State Research Agency through the Severo Ochoa and María de Maeztu Program for Centers and Units of Excellence in Research and Development (Dr Zanin); and from the Universitat de Valencia (Drs Iftimi and Lozano).