Background: Maintaining the patient awake and not intubated during the venovenous extracorporeal membrane oxygenation (VV ECMO) reduces the risk of ventilation-induced lung injury in patients with ARDS. Currently, there is a lack of data on outcomes and complications associated with the awake ECMO approach.Objectives: To evaluate outcomes and the occurrence of complications of awake ECMO approach guided by local safety protocol comprising ultrasound-guided cannulation, argatroban-based anticoagulation, respiratory support, and routine sedation targeted to reduce respiratory effort and keeping nurse-to-patient ratio of 1:1.Design: A single-center retrospective case series analysis.Methods: Consecutive patients with COVID-19-related acute respiratory distress syndrome (ARDS) (CARDS) treated by full awake VV ECMO approach from April 2019 to December 2023 were eligible.Results: Our center treated 10 patients (mean age 54.7 +/- 11.6 years) with CARDS with an awake ECMO approach. The reasons for awake ECMO included the presence of barotrauma in six patients, a team consensus to prefer awake ECMO instead of mechanical ventilation in three patients, and the patient's refusal to be intubated in one case. Before ECMO, patients were severely hypoxemic, with a mean value of Horowitz index of 48.9 +/- 9.1 mmHg and a mean respiratory rate of 28.8 +/- 7.3 breaths per minute on high-flow nasal cannula or noninvasive ventilation support. The mean duration of awake VV ECMO was 558.0 +/- 173.6 h. Seven patients (70%) were successfully disconnected from ECMO and fully recovered. Intubation from respiratory causes was needed in three patients (30%), all of whom died eventually. In total, three episodes of delirium, two episodes of significant bleeding, one pneumothorax requiring chest tube insertion, and one oxygenator acute exchange occurred throughout the 5580 h of awake ECMO. No complications related to cannula displacement or malposition occurred.Conclusion: The awake ECMO strategy guided by safety protocol appears to be a safe approach in conscious, severely hypoxemic, non-intubated patients with COVID-19-related ARDS. Enhancing the safety and effectiveness of extracorporeal membrane oxygenation (ECMO) therapy in awake, spontaneously breathing patients with the most severe form of COVID-19-related acute respiratory distress syndrome (ARDS)Why Was the Study Done? Extracorporeal membrane oxygenation (ECMO) represents a life-saving therapeutic approach that ensures appropriate gas exchange in patients with the most severe form of respiratory failure - acute respiratory distress syndrome (ARDS). Typically, patients are connected to ECMO when already deeply sedated and mechanically ventilated. The awake ECMO approach (keeping the patient awake, not intubated, and breathing spontaneously during ECMO support) minimizes the risks associated with mechanical ventilation and provides several relevant physiological benefits. However, the awake ECMO approach is also associated with several significant risks, including delirium, bleeding, and cannula displacement. Published papers have reported relatively frequent complications and method failures. What Did the Researchers Do? To address safety concerns regarding the awake ECMO approach, we present a single-center retrospective analysis of ten COVID-19-related ARDS patients treated with the awake ECMO approach, guided by the local safety protocol. What Did the Researchers Find? The awake ECMO approach yielded success (i.e., the patient was not intubated for respiratory causes, was successfully disconnected from ECMO, and fully recovered in seven patients (70.0%), outperforming previously published efficacy ranges. Three patients were intubated due to the progression of respiratory failure and eventually died. The incidence of adverse events during the 5,580 hours of awake ECMO was considered low. No cannula displacement or malposition occurred despite routine active physiotherapy, including walking during ECMO treatment in three patients. What Do the Findings Mean? The general applicability of the study is limited by the low number of patients and the retrospective monocentric design. However, the presented data illustrate real-life clinical scenarios and could aid clinicians in managing severely hypoxemic but still conscious and cooperative patients.