Cytokine release syndrome (CRS) is immune dysregulation phenomenon that is associated with immune checkpoint inhibitors. It is still difficult to distinguish CRS from other dangerous, acute and life-threatening medical disorders.We present a case of delayed grade 4 CRS following treatment of lung adenocarcinoma with ipilimumab plus nivolumab that warranted intensive care level treatment with abundant fluid resuscitation, two-tire vasopressor support, high-flow nasal oxygenation, corticosteroids in high dosages, as well as sustained low-efficiency daily diafiltration with CytoSorb hemadsorption and tocilizumab. Initial treatment of presumed septic shock of unknown origin did not yield results.After initiation of corticosteroids and particularly CytoSorb hemadsorption and tocilizumab, prompt clinical and laboratory improvement was observed.