Emphysematous bullae are a complication of end-stage COPD. Patients with large bullae and poor respiratory function have limited treatment options. Surgical resection is a recognized treatment, but functional improvement after bullectomy is not satisfactory in patients with forced expiratory volume in 1 s (FEV1) < 35% predicted. When this 59-year-old male end-stage COPD patient was assessed, he was cachectic and lung function tests showed a FEV1 of 0.56 L (19% predicted) and a RV of 7 L (314% predicted), while 6MWT was 315 m and MRC dyspnea score was 4. Chest X-ray revealed a massive bulla of 10 cm in diameter in the right middle lobe. A fibrobronchoscopy was performed under local anesthesia and 2 Zephyr 4.0 valves were placed in the right middle lobe. Chest X-ray and CT scan performed 36 days later showed the complete resolution of the bulla. Seven months later, the patient demonstrated an improvement in FEV1 (+30%) and a decrease in RV from 314 to 262% predicted. This case report shows that the Zephyr valves may be successfully used to treat a large bulla in the right middle lobe in a patient with diffuse emphysema and severely impaired lung function.