Abstract: www.nature.com/scientificreports OPEN The ‘myth of Hydroxychloroquine (HCQ) as post‑exposure prophylaxis (PEP) for the prevention of COVID‑19’ is far from reality Deba Prasad Dhibar 1,5*, Navneet Arora 1, Deepak Chaudhary 1, Ajay Prakash 2, Bikash Medhi 2, Neeraj Singla 1, Ritin Mohindra 1, Vikas Suri 1, Ashish Bhalla 1, Navneet Sharma 1, Mini P. Singh 3, P. V. M. Lakshmi 4, Kapil Goyal 3 & Arnab Ghosh 3 The efficacy of Hydroxychloroquine (HCQ) as post-exposure prophylaxis (PEP) for the prevention of COVID-19 was contentious. In this randomized control double-blind clinical trial, asymptomatic individuals with direct contact with laboratory-confirmed COVID-19 cases were randomized into PEP/ HCQ (N = 574) and control/placebo (N = 594) group. The PEP/HCQ group received tablet HCQ 400 mg q 12 hourly on day one followed by 400 mg once weekly for 3 weeks, and the control/Placebo group received matching Placebo. The incidence of COVID-19 was similar (p = 0.761) in PEP [N = 24 out of 574, (4.2%)] and control [N = 27 out of 594, (4.5%)] groups. Total absolute risk reduction for the incidence of new-onset COVID-19 was -0.3% points with an overall relative risk of 0.91 (95% confidence interval, 0.52 to 1.60) and the number needed to treat (NNT) was 333 to prevent the incident of one case of COVID-19. The study found that, PEP with HCQ was not advantageous for the prevention of COVID19 in asymptomatic individuals with high risk for SARS-CoV-2 infection. Though HCQ is a safer drug, the practice of irrational and indiscriminate use of HCQ for COVID-19 should be restrained with better pharmacovigilance. The novel corona virus (SARS-CoV-2) pandemic affected more than 575 million people worldwide with more than 6.3 million loss of life, as of 2nd August 2­ 0221. Globally, after the USA India is the second worst devastated country from COVID-19, with more than 44 million affected population and more than 526 thousand fatalities, as of 2nd August 2­ 0222. The clinical presentation of the COVID-19 ranges from asymptomatic or mild influenzalike illness, isolated or associated thrombotic/ischemic events to severe pneumonia with acute respiratory distress syndrome (ARDS) and subsequent secondary infection, sepsis, and multi-organ dysfunction syndrome (MODS) contributing to the ­mortality3. When the study was carried out, there were no definitive therapeutic drugs available for the treatment of COVID-19. COVID-19 patients used to be managed with symptomatic and supportive care only, which includes mechanical ventilation, antibiotics for secondary infection, anti-inflammatory or immune-modulators for the hyperimmune response, and blood thinner to combat thrombotic e­ vents4. Many drugs, Ribavirin, Lopinavir, Remdesivir, Molnupiravir, Chloroquine, Hydroxychloroquine, Azithromycin, Ivermectin, Tocilizumab, were explored or investigated but the majority of them turned out to be ineffective or partially effective for the treatment of COVID-19 and prevention of m ­ ortality5–7. In late 2021, oral antiviral drugs like, Paxlovid, Molnupiravir received emergency use authorization from the US Food and Drug Administration (FDA) for mild to moderate cases of early COVID-19, as in randomized control clinical trials (RCT) it was found to reduce the risk of hospitalization or ­death8,9. Sotrovimab, a monoclonal antibody also received emergency use authorization from the FDA for mild to moderate COVID-19 cases but was later found to be ineffective against the predominant..