Despite the lack of real antiviral evidence related to HCQ administration, this drug has also been investigated as a possible prophylactic agent. In fact, the pharmacokinetics of HCQ, like its long half-life and the high concentration in the lung (500-times higher than blood concentration), has made it an ideal candidate for prophylactic use [56]. The first study conducted on this line was performed in South Korea on 211 virus-exposed individuals, including 189 patients and 22 care-workers. The HCQ administration (400 mg day) as post-exposure prophylaxis resulted in the negative follow-up PCR tests after the end of 14 days of quarantine period (only 97.4% of patients and 95.5% of care-workers completed the study) [40]. However, it is necessary to consider that this is a single-center clinical study with a high risk of bias and that a subsequent randomized clinical study has denied it. In particular, Boulware D.R. et al., in a randomized, double-blind, placebo-controlled trial, tested HCQ as a prophylactic agent within 4 days after virus exposure. There were 821 asymptomatic participants randomly assigned to receive either placebo or HCQ (800 mg once, followed by 600 mg in 6 to 8 h, then 600 mg per day for 4 additional days). After 14 days of treatment, it was demonstrated that HCQ did not prevent COVID-19 infection when compared to placebo, since the incidence of illnesses compatible with Covid-19 disease did not differ significantly between subjects receiving HCQ (49 of 414 (11.8%)) or placebo (58 of 407 (14.3%)). Furthermore, the onset of side effects was more frequent in patients treated with HCQ than placebo (40.1% vs. 16.8%) [41]. To better assess the incidence of side effects linked to HCQ administration as post-exposure prophylaxis, a cross-sectional study was conducted among 140 doctors. Sixty nine adverse events were documented in 44 subjects (31%); the most common reported symptoms were headache followed by nausea, dizziness, abdominal cramps, and loose stools, while hypoglycemia was seen in only three diabetic participants [57]. Hence, even if the side effects highlighted were not serious, it is recommended to take the utmost care before using HCQ for COVID-19 chemoprophylaxis. The ineffectiveness of HCQ administration as post-exposure prophylaxis has also been demonstrated by an in vivo study on macaques. Maisonnasse P. et al. tested different treatment strategies, including HCQ alone or in combination with AZM, in comparison to placebo. All the treatments were administrated before or after viral load. It was seen that when HCQ was administrated as pre-exposure prophylaxis, it did not protect against the acquisition of the infection. Similarly, neither HCQ nor HCQ + AZM had beneficial effects in improving viral infection’s symptoms [58], confirming previously analyzed clinical studies’ negative results. Several case reports have supported all these results since people already using HCQ for a long time to treat inflammatory diseases also showed severe illness related to COVID-19 [59,60].