Abstract-Historically, persons with paralysis have limited options for overground ambulation. Recently, powered exoskeletons, which are systems that translate the user's body movements to activate motors that move the lower limbs through a predetermined gait pattern, have become available. As part of an ongoing clinical study (NCT01454570), eight nonambulatory persons with paraplegia were trained to ambulate with a powered exoskeleton. Measurements of oxygen uptake (VO 2 ) and heart rate (HR) were recorded for 6 min each during each maneuver while sitting, standing, and walking. The average value of VO 2 during walking (11.2 +/-1.7 mL/kg/min) was significantly higher than for sitting and standing (3.5 +/-0.4 and 4.3 +/-0.9 mL/kg/min, respectively; p < 0.001). The HR response during walking was significantly greater than that of either sitting or standing (118 +/-21 vs 70 +/-10 and 81 +/-12 beats per minute, respectively; p < 0.001). Persons with paraplegia were able to ambulate efficiently using the powered exoskeleton for overground ambulation, providing the potential for functional gain and improved fitness.Clinical Trial Registration: ClinicalTrials.gov; NCT01454570; "The ReWalk Exoskeletal Walking System for Persons with Paraplegia (VA_ReWalk)"; https://clinicaltrials.gov/ct2/show/ NCT01454570