© 2018 by the American Thoracic Society. Rationale: This is the first multicenter randomized controlled trial to evaluate the effectiveness and safety of Zephyr Endobronchial Valve (EBV) in patients with little to no collateral ventilation out to 12 months. Objectives: To evaluate the effectiveness and safety of Zephyr EBV in heterogeneous emphysema with little to no collateral ventilation in the treated lobe. Methods: Subjects were enrolled with a 2:1 randomization (EBV/standard of care [SoC]) at 24 sites. Primary outcome at 12 months was the ΔEBV-SoC of subjects with a post-bronchodilator FEV1 improvement from baseline of greater than or equal to 15%. Secondary endpoints included absolute changes in postbronchodilator FEV1, 6-minute-walk distance, and St. George's Respiratory Questionnaire scores. Measurements and Main Results: A total of 190 subjects (128 EBV and 62 SoC) were randomized. At 12 months, 47.7% EBV and 16.8% SoC subjects had a ΔFEV1 greater than or equal to 15% (P, 0.001). ΔEBV-SoC at 12 months was statistically and clinically significant: For FEV1, 0.106 L (P,0.001); 6-minute-walk distance, 139.31 m (P = 0.002); and St. George's Respiratory Questionnaire, 27.05 points (P = 0.004). Significant ΔEBV-SoC were also observed in hyperinflation (residual volume, 2522 ml; P,0.001), modified Medical Research Council Dyspnea Scale (20.8 points; P,0.001), and the BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index (21.2 points). Pneumothorax was the most common serious adverse event in the treatment period (procedure to 45 d), in 34/128 (26.6%) of EBV subjects. Four deaths occurred in the EBV group during this phase, and one each in the EBV and SoC groups between 46 days and 12 months. Conclusions: Zephyr EBV provides clinically meaningful benefits in lung function, exercise tolerance, dyspnea, and quality of life out to at least 12 months, with an acceptable safety profile in patients with little or no collateral ventilation in the target lobe. Clinical trial registered with www.clinicaltrials.gov (NCT 01796392).