The heterogeneity of COVID-19 lies within its diverse symptoms and severity, ranging from mild to lethal. Acute respiratory distress syndrome (ARDS) has been shown to be the leading cause of mortality in COVID-19 patients, characterized by a hyper cytokine storm. Autoimmunity is proposed to occur as a result of COVID-19, given the high similarity of the immune responses observed in COVID-19 and autoimmune diseases. Here, we investigate the level of autoimmune antibodies in COVID-19 patients with different severities. Initial screening for antinuclear antibodies (ANA) IgG revealed that 1.6% (2/126) and 4% (5/126) of ICU COVID-19 cases developed strong and moderate ANA levels, respectively. However, all the non-ICU cases (n=273) were ANA negative. The high ANA level was confirmed by immunofluorescence (IFA) and large-scale autoantibody screening by phage immunoprecipitation-sequencing (PhIP-Seq). Indeed, the majority of the samples showed "speckled" ANA pattern by microscopy, and we demonstrate that samples of ICU patients with strong and moderate ANA levels contain autoantibody specificities that predominantly targeted proteins involved in intracellular signal transduction, metabolism, apoptotic processes, and cell death; further denoting reactivity to nuclear and cytoplasmic antigens. In conclusion, our results further support the notion of routine screening for autoimmune responses in COVID-19 patients, which might help improve disease prognosis and patient management. Further, results provide compelling evidence that ANA-positive individuals should be excluded from being donors for convalescent plasma therapy in the context of Covid-19.