<b><i>Background:</i></b> For selected patients with severe emphysema, bronchoscopic lung volume reduction with endobronchial valves (EBV) is recognized as an additional treatment option. In most trials investigating EBV treatment, patients with a very low diffusing capacity (DLCO) were excluded from participation. <b><i>Objectives:</i></b> Our goal was to investigate whether EBV treatment in patients with emphysema with a very low DLCO is safe and effective. <b><i>Methods:</i></b> This was a single-center retrospective analysis including patients with emphysema and a DLCO ≤20%pred who underwent EBV treatment. Follow-up was performed 6 months post-treatment. Outcome parameters were compared to a historical matched control group (DLCO &#x3e;20%pred, matched for sex, age, forced expiratory volume in 1 s [FEV₁], and residual volume [RV]). <b><i>Results:</i></b> Twenty patients (80% female, 64 ± 6 years, FEV₁ 26 ± 6%pred, RV 233 ± 45%pred, DLCO 18 ± 1.6%pred) underwent EBV treatment. At 6 months follow-up, we found a statistically significant improvement in FEV₁ (0.08 ± 0.12 L), RV (–0.45 ± 0.95 L), 6-min walking distance (38 ± 65 m), and St. George’s Respiratory Questionnaire (–12 ± 13 points). With the exception of FEV₁, all exceeded the minimal clinically important difference. The most common serious adverse event was a pneumothorax requiring intervention (15%). There were no significant differences in outcome compared to the DLCO &#x3e;20%pred control group. <b><i>Conclusions:</i></b> In this single-center retrospective analysis, we showed statistically significant and clinically relevant improvements in lung function, exercise capacity, and quality of life up to 6 months after EBV treatment in emphysema patients with a DLCO ≤20% (14–20%) of predicted with no increased risk of serious adverse events.