ObjectivesThe CytoSorb therapy in COVID-19 (CTC) registry evaluated the clinical performance and treatment parameters of extracorporeal hemoadsorption integrated with veno-venous extracorporeal membrane oxygenation (VV ECMO) in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) and respiratory failure under US FDA Emergency Use Authorization.DesignMulticenter, observational, registry (NCT04391920).SettingIntensive care units (ICUs) in five major US academic centers between April 2020 and January 2022.PatientsA total of 100 critically ill adults with COVID-19-related ARDS requiring VV ECMO support, who were treated with extracorporeal hemoadsorption.InterventionsNone.Measurements and main resultsBaseline demographics, clinical characteristics, laboratory values and outcomes were recorded following individual ethics committee approval at each center. Detailed data on organ support utilization parameters and hemoadsorption treatments were also collected. Biomarker data were collected according to the standard practice at each participating site, and available values were compared before and after hemoadsorption. The primary outcome of mortality was evaluated using a time-to-event analysis. A total of 100 patients (63% male; age 44 ± 11 years) were included. Survival rates were 86% at 30 days and 74% at 90 days. Median time from ICU admission to the initiation of hemoadsorption was 87 h and was used to define two post hoc groups: ≤ 87 h (group-early start,GE) and > 87 h (group-late start,GL). After the start of hemoadsorption, patients in theGEversusGLhad significantly shorter median duration of mechanical ventilation (7 [2–26] vs. 17 [7–37] days,p= 0.02), ECMO support (13 [8–24] vs. 29 [14–38] days,p= 0.021) and ICU stay (17 [10–40] vs 36 [19–55] days,p= 0.002). Survival at 90 days inGEwas 82% compared to 66% in GL(p= 0.14). No device-related adverse events were reported.ConclusionsIn critically ill patients with severe COVID-19-related ARDS treated with the combination of VV-ECMO and hemoadsorption, 90-day survival was 74% and earlier intervention was associated with shorter need for organ support and ICU stay. These results lend support to the concept of “enhanced lung rest” with the combined use of VV-ECMO plus hemoadsorption in patients with ARDS.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13054-023-04517-3.