Patients with chronic kidney disease treated by in-center conventional hemodialysis (3 times per week) have significant impairments in health-related quality of life measures, which have been associated with increased morbidity and mortality. FREEDOM is an ongoing prospective cohort study measuring the potential benefits of at-home short daily (6 times per week) hemodialysis. In this interim report we examine the long-term effect of short daily hemodialysis on health-related quality of life, as measured by the SF-36 health survey. This was administered at baseline, 4 and 12 months after initiation of short daily hemodialysis to 291 participants (total cohort), of which 154 completed the 12-month follow-up (as-treated cohort). At the time of analysis, the mean age was 53 years, 66% were men, 58% had an AV fistula, 90% transitioned from in-center hemodialysis, and 45% had diabetes mellitus. In the total cohort analysis, both the physical- and mental-component summary scores improved over the 12-month period, as did all 8 individual domains of the SF-36. The as-treated cohort analysis showed similar improvements with the exception of the role-emotional domain. Significantly, in the as-treated cohort, the percentage of patients achieving a physical-component summary score at least equivalent to the general population more than doubled. Hence, at-home short daily hemodialysis is associated with long-term improvements in various physical and mental health-related quality of life measures.