Aim. To compare the cases reported to the Spanish Pharmacovigilance System (SEFV-H) with HCQ used in COVID-19 vs. HCQ used in other indications. Methods. All cases of adverse drug reactions (ADR) submitted to the Spanish Pharmacovigilance database (FEDRA) from 1 January 1982 to 19 February 2021 suspected to be induced by HCQ were identified. Cases were classified into two groups: no-Covid patients and Covid patients. Frequencies of ADR were compared. Reporting Odds Ratios (ROR) with its lower limit of the 95% confidence interval (-ROR) and Omega (Ω) and its lower limit of the 95% credibility interval (Ω -025) were obtained to estimate disproportionalities. Results. More severe cases were reported with the use of HCQ in Covid. Main differences in frequency were observed in hepatobiliary, skin, gastrointestinal, eye, nervous system and heart ADRs. During the Covid-19 pandemic, disproportionality was found for Torsade de Pointes/QT prolongation with a ROR (-ROR) of 132.8 (76.7); severe hepatotoxicity, 18.7 (14.7); dyslipidaemias, 12.1 (6.1); shock, 9.5 (6.9) and ischaemic colitis, 8.9 (2.6). Myopathies, haemolytic disorders and suicidal behaviour increased their disproportionality during the pandemic. Disproportionality was observed for neoplasms, haematopoietic cytopaenias and interstitial lung disease in the pre-Covid period. Ω showed potential interactions between HCQ and azithromycin, ceftriaxone, lopinavir and tocilizumab . Conclusions. The use of HCQ in Covid-19 changed its safety profile. Of particular concern during the pandemic were arrhythmias, hepatotoxicity, severe skin reactions and suicide risk, but not ocular disorders. Some ADRs identified as signals would require more detailed analyses.