Flail chest is an uncommon consequence of traumatic injury. Medical management includes mechanical ventilation for internal pneumatic stabilization. Control of respiratory drive is necessary to avoid paradoxical movement and impairment of recovery. Traditional approaches include sedation and neuromuscular blockade, but these measures are at odds with current trends of keeping patients awake and implementing active rehabilitation. We hypothesized that extracorporeal carbon dioxide removal (ECCO2R) would suppress the respiratory drive sufficiently to permit synchronous mechanical ventilation, allowing rib fracture healing in an awake patient with extensive bilateral flail chest. A patient with 21 fractures underwent ECCO2R for 6 weeks to permit internal pneumatic stabilization with mechanical ventilation, targeting a partial pressure of carbon dioxide in arterial blood (PaCO2) of 25-30 mm Hg. The first 2 weeks were performed with extracorporeal membrane oxygenation (ECMO) for bilateral pulmonary contusions and acute respiratory distress syndrome. The last 4 weeks was with low-flow ECCO2R. Respiratory drive was suppressed during both ECMO and ECCO2R phases when the targeted hypocapnia range of 25-30 mm Hg was achieved, permitting synchronous positive pressure ventilation in an awake and cooperative patient undergoing active rehabilitation. Extracorporeal carbon dioxide removal targeting hypocapnia is a potential adjunct in extensive flail chest injury undergoing nonsurgical management.