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Background Endoscopic lung volume reduction (ELVR) with valves has been suggested to be the key strategy for patients with severe emphysema and concomitant low diffusing capacity of the lung for carbon monoxide (DLCO). However, robust evidence is still missing. We therefore aim to compare clinical outcomes in relation to DLCO for patients treated with ELVR. Methods We assessed DLCO at baseline and 3 months follow-up and compared pre- and postprocedural pulmonary function test, quality of life, exercise capacity and adverse events. This is a retrospective subanalysis of prospectively collected data from the German Lung Emphysema Registry. Results In total, 121 patients treated with ELVR were analysed. Thirty-four patients with a DLCO ≤20% and 87 patients with a DLCO >20% showed similar baseline characteristics. After ELVR, there was a decrease of residual volume (both p<0.001 to baseline) in both groups, and both demonstrated better quality of life (p<0.01 to baseline). Forced expiratory volume in 1 s (FEV1) improved significantly only in patients with a DLCO >20% (p<0.001 to baseline). Exercise capacity remained almost unchanged in both groups (p=0.3). The most frequent complication for both groups was a pneumothorax (DLCO ≤20%: 17.6% versus DLCO >20%: 16.1%; p=0.728). However, there were no significant differences in other adverse events between both groups. Conclusions ELVR improves lung function as well as quality of life in patients with DLCO >20% and DLCO ≤20%. Adverse events did not differ between groups. Therefore, ELVR should be considered as a treatment option, even in patients with a very low DLCO.