BackgroundCytokine release syndrome (CRS) represents a potentially life-threatening and systematic inflammatory response where it is noted an increase of secretion of proinflammatory cytokines from lymphocytes, myeloid cells like macrophages, dendritic cells, and monocytes. This syndrome is characteristic of some conditions such as viral infections, administration of antibody-based therapy, auto immune disease, and immunotherapy, especially in severe COVID-19 patients.Case reportsWe presented two cases of COVID-19 patients in which the clinical picture significantly deteriorated during hospitalization, where the value of CRP, ferritin, LDH, and IL-6 dramatically increased, especially values of IL-6 were recorded over 2000. We treated them with third-generation cephalosporins, carbapenems, glycopeptides, metronidazole, anti-IL-6 inhibitor, low molecular weight heparin (LMWH), glucocorticoids, immunoglobulins (IVIG), and vitamins. Both patients were successfully treated and were discharged from the hospital with a recommendation for oral anticoagulant therapy.ConclusionCRS is a complex syndrome. In the future, it is necessary to educate doctors about this syndrome, as well as to develop drugs whose goal would be to reduce the inflammatory response in already developed diseases.