Aim: CQ and HCQ are currently being investigated worldwide for their clinical efficacy against COVID-19, however a major concern regarding these drugs remains their safety profile. The aim of the present study was to identify potential safety signals of CQ and HCQ use, in the period prior to their repurpose as COVID-19 treatment options analyzing safety data retrieved from the FDA Adverse Event Reporting System (FAERS) pharmacovigilance database. Methods: We performed a disproportionality analysis of all available FAERS data between the first quarter of 2004 and December 2019 using the OpenVigil2.1-MedDRA software. Disproportionality was quantified using the reporting odds ratio (ROR) and its 95% confidence interval (CIs). The reporting mortality of CQ and HCQ was also investigated Results: The dataset contained 6,635,356 reports. Based on the comparison of the RORs, significant differences were observed between CQ and HCQ for most of the adverse events: cardiomyopathy, cardiac arrhythmias, retinal disorders, corneal disorders, hearing disorders, headache, hepatic disorders, severe cutaneous reactions, musculoskeletal disorders and cytopenia. Only CQ was significantly associated with psychotic disorders, suicide and self-injury, convulsions, peripheral neuropathy and decreased appetite. In multivariable logistic regression, outcome death was more frequently associated with CQ users, generally older females, with co-reported suicide and self-injury, cardiomyopathy, cardiac arrhythmias and decreased appetite. Discussion: Our results suggest that HCQ has a safer clinical profile compared to CQ, especially regarding cardiotoxicity and thus could serve as a safer therapeutic approach in COVID-19. However, until more real-world and RCTs’ data are available, close supervision is strongly recommended.