Introduction: The idea of using extracorporeal cytokine adsorption therapy (ECAT) is to remove cytokines from the blood in order to restore a balanced immune response. Yet, it is unclear as to whether the use of ECAT improves patient-relevant outcomes. Hence, the aim of this article is to synthesize the currently available evidence with regard to a potential clinical benefit of ECAT used in cardiac surgery or sepsis.Methods: We conducted an updated systematic review summarizing the body of evidence with regard to a potential clinical benefit of ECAT. The study followed the PRISMA statement and the European Network for Health Technology Assessment (EUnetHTA) guidelines. The quality of the individual studies and the strength of the available evidence was assessed using the Cochrane risk of bias tool (v.1) and the GRADE approach respectively. Mortality, organ function, length of stay in the intensive care unit and length of hospitalization, as well as adverse events, were defined as critical outcomes.Results: For the preventive treatment of ECAT in patients undergoing cardiac surgery, we found very low-quality inconclusive evidence for mortality (5 randomized controlled trials (RCTs), n = 163), length of stay in the intensive care unit (5 RCTs, n = 163), and length of hospitalization (3 RCTs, n = 101). In addition, very low-quality inconclusive evidence was found for (serious) adverse events (4 RCTs, n = 148). For the therapeutic treatment of ECAT in patients with sepsis/ septic shock, we found very low-quality inconclusive evidence for mortality up to 60-day follow-up (2 RCTs, n = 117), organ function (2 RCTs, n = 117) and length of stay in the intensive care unit (1 study, n = 20). Similarly, very low-quality inconclusive evidence was found for (serious) adverse events (2 RCTs, n = 117). There are currently eighteen ongoing RCTs on the use of ECAT.Conclusions: There is a lack of reliable data on the clinical benefit of using ECAT as an add-on treatment preventively in cardiac surgery and therapeutically in patients with sepsis or septic shock. While theoretical advantages are anticipated, the current available evidence is inconclusive and was not able to establish the efficacy and safety of ECAT in combination with standard care in the investigated indications. In light of the available RCTs, we strongly recommend the consideration of studies with patient-relevant endpoints and adequate statistical power, instead of investing further research funds on small studies that may not shed more light onto the potential clinical benefit of ECAT. The results of ongoing RCTs are awaited to guide the decision on whether further research funds should be invested in ECAT research or to conclude that the intervention may not show clinical benefits for patients.