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Background: Protective effects of Bacillus Calmette–Guérin (BCG) vaccination and clofazimine and dapsone treatment against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported. Patients at risk for leprosy represent an interesting model for assessing the effects of these therapies on the occurrence and severity of coronavirus disease 2019 (COVID-19). We assessed the influence of leprosy-related variables in the occurrence and severity of COVID-19. Methodology/Principal findings: We performed a 14-month prospective real-world cohort study in which the main risk factor was 2 previous vaccinations with BCG and the main outcome was COVID-19 detection by reverse transcription polymerase chain reaction (RT-PCR). A Cox proportional hazards model was used. Among the 406 included patients, 113 were diagnosed with leprosy. During follow-up, 69 (16.99%) patients contracted COVID-19. Survival analysis showed that leprosy was associated with COVID-19 (p<0.001), but multivariate analysis showed that only COVID-19-positive household contacts (hazard ratio (HR) = 8.04; 95% CI = 4.93–13.11) and diabetes mellitus (HR = 2.06; 95% CI = 1.04–4.06) were significant risk factors for COVID-19. Conclusions/Significance: Leprosy patients are vulnerable to COVID-19 because they have more frequent contact with SARS-CoV-2-infected patients, possibly due to social and economic limitations. Our model showed that the use of corticosteroids, thalidomide, pentoxifylline, clofazimine, or dapsone or BCG vaccination did not affect the occurrence or severity of COVID-19. Author summary: Leprosy is a chronic infectious disease caused by Mycobacterium leprae and Mycobacterium lepromatosis. Coronavirus disease 2019 (COVID-19) results in an intense inflammatory response that is dependent on several immune mediators. Since the beginning of the COVID-19 pandemic, an interaction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and M. leprae infection has been considered a possibility. Protective effects of Bacillus Calmette–Guérin (BCG) vaccination and clofazimine and dapsone treatment against SARS-CoV-2 infection have been reported. Patients at risk for leprosy represent an interesting model for assessing the effects of these therapies on the occurrence and severity of COVID-19. We assessed the influence of leprosy-related variables in the occurrence and severity of COVID-19. We performed a 14-month study. Among the 406 included patients, 113 were diagnosed with leprosy. During follow-up, 69 (16.99%) patients contracted COVID-19. Our analysis showed that only COVID-19-positive household contacts and diabetes mellitus were significant risk factors for COVID-19. Leprosy patients are vulnerable to COVID-19 because they have more frequent contact with SARS-CoV-2-infected patients, possibly due to social and economic limitations. Our model showed that the use of clofazimine or dapsone or BCG vaccination did not affect the occurrence or severity of COVID-19. [ABSTRACT FROM AUTHOR]