Background COVID-19, caused by the virus SARS-CoV-2, has brought extensive challenges to the scientific community in recent months. Several studies have been undertaken in an attempt to minimize the impact of the disease worldwide. Although new knowledge has been quickly disseminated, including viral mechanisms, pathophysiology, and clinical findings, there is a lack of information on the effective pharmacological management of this disease. In vitro studies have shown some benefits related to the use of antimalarials (chloroquine and hydroxychloroquine) for inhibiting SARS-CoV-2. However, the data from open clinical trials on COVID-19 patients are controversial. Objective We present the protocol for a research project that compares the potential protective effect of antimalarials in preventing moderate-to-severe forms of COVID-19 in two groups: (1) patients treated chronically with antimalarials for rheumatic diseases and (2) other members of the patients’ household who have not been diagnosed with rheumatic diseases and are not taking antimalarials. Methods This is a 24-week, prospective, observational cohort study comprising patients from public and private health services across Brazil, who chronically use antimalarials for the treatment of immune-mediated rheumatic diseases, osteoarthritis, or chikungunya-related arthropathy. A total of six sequential phone interviews were scheduled during the COVID-19 outbreak in five different regions of Brazil. Information regarding social, epidemiological, and demographic data, as well as details about rheumatic diseases, antimalarials, comorbidities, and concomitant medication, is being recorded using a specific online form in the REDCap database. Symptoms suggestive of COVID-19, including fever, cough, dyspnea, anosmia, and dysgeusia, are being self-reported and collected via phone interviews. Our main outcomes are hospitalization, need of intensive care unit, and death. Results Recruitment began at the end of March 2020, and the inclusion was done during an 8-week period (from March 29 to May 17) with a total of 10,443 individuals enrolled at baseline, 5166 of whom have rheumatic diseases, from 23 tertiary rheumatology centers across 97 Brazilian cities. Data analysis is scheduled to begin after all inclusion data have been collected. Conclusions This study, which includes a large sample of chronic antimalarial users, will allow us to explore whether SARS-CoV-2 infection may be associated with immune-mediated rheumatic diseases and long-term antimalarial usage. Trial Registration Brazilian Registry of Clinical Trials RBR–9KTWX6; http://www.ensaiosclinicos.gov.br/rg/RBR-9ktwx6/ International Registered Report Identifier (IRRID) DERR1-10.2196/23532