Home hemodialysis has been a therapeutic option for almost 4 decades. The complexity of dialysis equipment has been a factor-limiting adoption of this modality. We performed a feasibility study to demonstrate the safety of center-based vs. home-based daily hemodialysis with the NxStage System One portable hemodialysis device. We also performed a retrospective analysis to determine if clinical effects previously associated with short-daily dialysis were also seen using this novel device. We conducted a prospective, 2-treatment, 2-period, open-label, crossover study of in-center hemodialysis vs. home hemodialysis in 32 patients treated at 6 U.S. centers. The 8-week In-Center Phase (6 days/week) was followed by a 2-week transition period and then followed by the 8-week Home Phase (6 days/week). We retrospectively collected data on hemodialysis treatment parameters immediately preceding the study in a subset of patients. Twenty-six out of 32 patients (81%) successfully completed the study. Successful delivery of at least 90% of prescribed fluid volume (primary endpoint) was achieved in 98.5% of treatments in-center and 97.3% at home. Total effluent volume as a percentage of prescribed volume was between 94% and 100% for all study weeks. The composite rate of intradialytic and interdialytic adverse events per 100 treatments was significantly higher for the In-Center Phase (5.30) compared with the Home Phase (2.10; p=0.007). Compared with the period immediately preceding the study, there were reductions in blood pressure, antihypertensive medications, and interdialytic weight gain. Daily home hemodialysis with a small, easy-to-use hemodialysis device is a viable dialysis option for end-stage renal disease patients capable of self/partner-administered dialysis.