BACKGROUND Lung volume reduction surgery (LVRS) has been proven to be a successful procedure and can be performed with low mortality when defined selection criteria are met. We hypothesized good outcome and low mortality after LVRS for selected patients with severe hyperinflation and nonhomogeneous morphology even when diffusion capacity of the lung for carbon monoxide (Dlco) is less than 20%. METHODS The study included all patients scheduled for LVRS between March 2005 and May 2014 with a preoperative Dlco of less than 20%. Postoperative 90-day mortality was the primary end point. Secondary end points were postoperative lung function and surgical morbidity at 3, 6, and 12 months. RESULTS Included were 33 patients with a median forced expiratory volume in 1 second of 23% (interquartile range, 19% to 28%), a median diffusion capacity of 15% (interquartile range, 13% to 18%), and a median hyperinflation of 76% (residual volume-to-total lung capacity ratio of 70% to 76%). Mean follow-up was 44.8 months (range, 10 to 141 months). Heterogeneous emphysema was present in 26 patients, and 7 showed intermediately heterogeneous morphology. Sixteen procedures were bilateral, and 31 were performed by video-assisted thoracoscopic surgery. The 90-day mortality was 0%. Median forced expiratory volume in 1 second percentage predicted at 3 months increased from 23% to 29% (p < 0.001). Median Dlco increased from 15% to 24% (p < 0.001), and median hyperinflation decreased from 76% to 63% (p < 0.001). A prolonged air leak exceeding 7 days occurred in 16 patients (48.5%), and 6 required reoperation for fistula closure. The 7 patients with intermediately heterogeneous emphysema showed a median increase in forced expiratory volume in 1 second from 20% preoperatively to 28% postoperatively (p = 0.028). CONCLUSIONS Selected patients with severely impaired Dlco of less than 20% can cautiously be considered as potential candidates if hyperinflation is severe and the lungs show areas with advanced destruction as targets for resection.