The early phase of the COVID-19 pandemic prompted a repurposing of antiviral and immunomodulatory drugs as investigational therapeutics, including hydroxychloroquine and chloroquine. While antimalarials have been well-refuted as a treatment for COVID-19, data on these drugs' role in preventing SARS-CoV-2 infection as pre-exposure prophylaxis is more limited. We investigated the efficacy of antimalarial drugs as pre-exposure SARS-CoV-2 prophylaxis in a US tertiary-care center. We identified all adult patients exposed to antimalarials with active prescriptions from July 1, 2019 to February 29, 2020 and exact-matched antimalarial-treated study patients with controls on age, sex, race, and Charleston Comorbidity Index. We used multivariable logistic regression to calculate the odds ratio (OR) of COVID-19 diagnosis by antimalarial exposure, adjusting for demographics, comorbidities, local infection rates, and specific conditions identified in early studies as risk factors for COVID-19. There were 3,074 patients with antimalarial prescriptions and 58,955 matched controls. Hydroxychloroquine represented 98.8% of antimalarial prescriptions. There were 51 (1.7%) infections among antimalarial-exposed and 973 (1.6%) among controls. No protective effect for SARS-CoV-2 infection was demonstrated among antimalarial-exposed patients in the multivariate model (OR=1.06, 95% CI 0.80-1.40, P=0.70). These findings corroborate prior work demonstrating that hydroxychloroquine and related antimalarials do not have a role in protection against SARS-CoV-2.Klebanov N, Pahalyants V, Said JT, et al. Antimalarials are not effective as pre-exposure prophylaxis for COVID-19: a retrospective matched control study. J Drugs Dermatol. 2023;22(8):840-843. doi:10.36849/JDD.6593.