Extracorporeal carbon dioxide removal (ECCO₂R) prevents intubation and facilitates extubation in patients with hypercapnic respiratory failure. However, low-flow systems increase shear stress and need full anticoagulation, increasing the risk of circuit-related complications. We assessed the safety and efficacy of a high-caliber dual-lumen cannula, designed for jugular veno-venous extracorporeal membrane oxygenation (VV ECMO), repurposed for femoral vein insertion, with the aim of achieving higher blood-flow rates and more efficient CO₂ clearance. We retrospectively analyzed 16 intensive care unit (ICU) patients (62 years; 81% chronic obstructive pulmonary disease [COPD]) treated with ECCO₂R using a large-caliber dual-lumen cannula (20–23 Fr) inserted via the femoral vein. Key outcomes included changes in gas exchange, ventilatory support status, and complications. Extracorporeal carbon dioxide removal enabled rapid CO₂ clearance, with arterial carbon dioxide pressure (PaCO₂) decreasing from 68 [62–95] to 49 [45–56] mm Hg at 2 h, and pH increasing from 7.20 [7.16–7.27] to 7.36 [7.33–7.41]. Fifty-six percent of patients avoided intubation, whereas all intubated patients were extubated during ECCO₂R. The median support duration was 5 [4–7] days. No hemolysis was documented. One bleeding episode and one clotting event occurred; no thrombotic or cannulation-related complications were observed. Femoral vein cannulation with a large-caliber dual-lumen cannula for ECCO₂R appears feasible and safe. This strategy may offer technical and clinical advantages over conventional ECCO₂R systems, warranting prospective investigation.