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Background: Data on how SARS-CoV-2 enters and spreads in a population are essential for guiding public policies., Objective: This study seeks to understand the transmission dynamics of SARS-CoV-2 in small Brazilian towns during the early phase of the epidemic and to identify core groups that can serve as the initial source of infection as well as factors associated with a higher risk of COVID-19., Methods: Two population-based seroprevalence studies, one household survey, and a case-control study were conducted in two small towns in southeastern Brazil between May and June 2020. In the population-based studies, 400 people were evaluated in each town; there were 40 homes in the household survey, and 95 cases and 393 controls in the case-control study. SARS-CoV-2 serology testing was performed on participants, and a questionnaire was applied. Prevalence, household secondary infection rate, and factors associated with infection were assessed. Odds ratios (ORs) were calculated by logistic regression. Logistics worker was defined as an individual with an occupation focused on the transportation of people or goods and whose job involves traveling outside the town of residence at least once a week., Results: Higher seroprevalence of SARS-CoV-2 was observed in the town with a greater proportion of logistics workers. The secondary household infection rate was 49.1% (55/112), and it was observed that in most households (28/40, 70%) the index case was a logistics worker. The case-control study revealed that being a logistics worker (OR 18.0, 95% CI 8.4-38.7) or living with one (OR 6.9, 95% CI 3.3-14.5) increases the risk of infection. In addition, having close contact with a confirmed case (OR 13.4, 95% CI 6.6-27.3) and living with more than four people (OR 2.7, 95% CI 1.1-7.1) were also risk factors., Conclusions: Our study shows a strong association between logistics workers and the risk of SARS-CoV-2 infection and highlights the key role of these workers in the viral spread in small towns. These findings indicate the need to focus on this population to determine COVID-19 prevention and control strategies, including vaccination and sentinel genomic surveillance., (©Breno Bernardes-Souza, Saulo Ricardo Costa Júnior, Carolina Ali Santos, Raimundo Marques Do Nascimento Neto, Fernando De Carvalho Bottega, Daiana Carolina Godoy, Bruno Lourençoni Freitas, Daniela Leite Garcia Silva, Titus Josef Brinker, Raiza Aranha Nascimento, Unaí Tupinambás, Alexandre Barbosa Reis, Wendel Coura-Vital. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 01.09.2021.)