Patients with end-stage renal disease (ESRD) requiring renal replacement have impaired health-related quality of life (HRQoL), and there is general consensus that HRQoL improves with successful transplant and evidence of improvement with frequent hemodialysis. This study reports changes in HRQoL associated with changes in treatment modality to daily hemodialysis (DHD) and transplant among patients requiring renal replacement. This cohort study had assessments at baseline and 6-month following modality change. Subjects were nondiabetic individuals receiving conventional hemodialysis who (a) remained on conventional hemodialysis (n = 13), (b) changed to daily hemodialysis (DHD) (n = 10), or (c) received a living donor transplant (n = 20). Thirty-four healthy controls were assessed once for comparison. HRQoL was measured using the Kidney Disease Quality of Life Instrument. The Physical Functioning and Physical Composite Scale scores were primary outcomes. Transplantation resulted in significant improvements in six of eight generic scales and the physical composite scale (PCS). Those changing to DHD had significant improvements in Physical Function and PCS scales. Those remaining on dialysis remained lower than controls on all scales except for Vitality; the transplant group remained lower than controls only on the Vitality and General Health scales. Transplant resulted in significant improvements in four of the seven disease-specific scales (symptoms, effects, and burden of kidney disease, work). DHD resulted in improvements in the effects of kidney disease. Modality change to transplant results in significant improvement in HRQoL, achieving levels similar to controls. Change to daily hemodialysis improves only select HRQoL domains and remains low in disease-specific domains.