<p>Dataset.</p>

Rapid diagnostic self-tests have emerged as effective tools for identifying and controlling the spread of SARS-CoV-2. However, little is known about their acceptability and usability among populations under socioeconomic vulnerability globally. We aimed to evaluate the acceptability and usability of a COVID-19 antigen self-test among persons living in Salvador and Rio de Janeiro, Brazil. In this cross-sectional study (January–May 2023), participants used a COVID-19 antigen self-test in a simulated real-world setting, guided by an instructional video. Usability was assessed through two main outcomes: comprehension of instructions and proper execution of self-test (Poisson regression model); and accuracy in interpretation of self-test results (Cohen’s kappa). Acceptability was evaluated based on willingness to reuse the self-test, user experience, and recommendation to others. Among 437 participants, most were women (65.7%), self-identified as Black/Pardo (mixed-race) (81.5%), aged 35 + years (65.7%), had a household income ≤ USD 470 (70.0%) and had completed secondary education (46.2%). Despite some procedural difficulties, most participants obtained valid results (88.1%), higher in Salvador (95.2%) than in Rio de Janeiro (81.7%) (p < 0.001). Participants showed difficulty interpreting test results, particularly inconclusive with a positive mark (32.9% correct) and faint positive markers (25.2% correct). Accuracy in interpretation was 89.6%, with moderate to substantial inter-rater agreement (Cohen’s kappa = 0.56 overall, reaching 0.78 among participants aged 35–44 years). Participants with older age, lower education level and self-identified as men had lower likelihood of obtaining valid results in adjusted model, and increased difficulties in test setup and interpretation. Over 95% of participants were willing to reuse and recommended the self-test. This study revealed high acceptability and usability of the COVID-19 antigen self-test among populations under socioeconomic vulnerability in Brazil. However, misinterpretation poses public and individual health risks, underscoring the need of simplified, multimodal and accessible instructions.