Rationale: Biologic lung volume reduction (BioLVR) is a new endobronchial treatment for advanced emphysema that reduces lung volume through tissue remodeling. Objectives: Assess the safety and therapeutic dose of BioLVR hydrogel in upper lobe predominant emphysema. Methods: Open-labeled, multicenter phase 2 dose-ranging studies were performed with BioLVR hydrogel administered to eight sub-segmental sites (four in each upper lobe) involving: (1) low-dose treatment (n = 28) with 10 ml per site (LD); and (2) high-dose treatment (n = 22) with 20 ml per site (HD). Safety was assessed by the incidence of serious medical complications. Efficacy was assessed by change from baseline in pulmonary function tests, dyspnea score, 6-minute walk distance, and health-related quality of life. Measurements and Main Results: After treatment there were no deaths and four serious treatment-related complications. A reduction in residual volume to TLC ratio at 12 weeks (primary efficacy outcome) was achieved with both LD (-6.4 ± 9.3%; P = 0.002) and HD (-5.5 ± 9.4%; P = 0.028) treatments. Improvements in pulmonary function in HD (6 mo: ΔFEV1 = +15.6%; P= 0.002; ΔFVC = +9.1%; P = 0.034) were greater than in LD patients (6 mo: ΔFEV1 = +6.7%; P = 0.021; ΔFVC = +5.1%; P = 0.139). LD- and HD-treated groups both demonstrated improved symptom scores and health-related quality of life. Conclusions: BioLVR improves physiology and functional outcomes up to 6 months with an acceptable safety profile in upper lobe predominant emphysema. Overall improvement was greater and responses more durable with 20 ml per site than 10 ml per site dosing. Clinical trial registered with www.clinicaltrials.gov (NCT 00435253 and NCT 00515164).