Abstract Background Migrant populations in Central America face complex disease burdens, including respiratory viruses. A frequently overlooked sub-group within the migrant populations is the returned migrants. Assessment of COVID-19 disease burden and associated risk factors are important for identifying high-risk groups, as well as for informing disease reduction efforts, including vaccination programs. Methods As a sub-study within a larger (AGRI-CASA) cohort study, we screened and offered enrollment to returned migrants on a weekly basis in El Centro de Retornados de Ayutla, located in the Tecun Uman community along the Guatemala-Mexico border. The existing screening program includes symptomatic screening of all returnees for cough or fever; we then performed SARS-CoV-2 rapid antigen testing from nasopharyngeal swab on all symptomatic and 10% of asymptomatic individuals. In our sub-study of this screened population, we collected additional clinical and exposure data and a second mid-turbinate nasal swab on all consenting adults available with COVID-like illness (CLI). The samples underwent PCR testing at the Trifinio Center for Human Development (CHD) laboratory. We did not enroll minors due to uncertainty of legal guardians. Results From January-September 2023, 10,570 Guatemalans were deported through El Centro de Salud de Ayutla, of which 5,373 (50.8%) were tested for SARS-CoV-2 and 42 (0.8%) were positive, a decrease from 2021 (n=40,927 migrants, 12,181 tested, and 714 [5.9%) positive) and 2022 (n=36,865 migrants, 12,406 tested, 403 [3.2%] positive). Our sub-study enrolled 197 (30.1%) of 655 symptomatic participants with CLI from January-September 2023. Of those, median age (SD) was 26 (7.87) years and 174 (88%) were male. The most commonly reported symptoms were cough (34.5%) nasal congestion (27.9%), sore throat (21.3%), and headache (19.3%). Of 197 participants, 163 samples were available for testing; 4 (2.5%) of those were SARS-CoV-2 antigen positive via POC testing and 5 (3.1%) of those samples were PCR-positive at the Trifinio Center for Human Development (CHD) laboratory. The PCR-confirmed SARS-CoV-2 positive samples contained XBB1.15, XBB1.5.11, and XBB.1.5 variants. According to Guatemala’s Laboratorio Nacional de Salud, the main variant in the country in February and June 2023 was Omicron, especially the XBB variant. Conclusion Despite the crowding conditions for deported migrants returning from Mexico, SARS-CoV-2 positivity for symptomatic individuals was relatively low. Further studies should evaluate additional pathogens and migrants traveling in both directions to characterize the full disease burden of this vulnerable population. Combined with additional information on the vaccination status of the deported migrants, these results will be crucial in calculating the number-needed-to-vaccinate (NNV) among the departed migrant populations and the local Guatemalans as well as assessing the cost effectiveness of vaccination programs targeting these populations.