CONTEXT: Omidubicel is an ex vivo expanded stem cell product derived from umbilical cord blood (UCB) for allogeneic hematopoietic stem cell transplantation (allo-HSCT). A multicenter phase III trial demonstrated faster engraftment and fewer infections with omidubicel versus standard UCB. OBJECTIVE: To compare patient-reported health-related quality of life (HRQL) between omidubicel and UCB. DESIGN: Patients with hematologic malignancies undergoing allo-HSCT were randomized 1:1 to omidubicel or UCB between 2017-2020. Validated HRQL surveys (FACT-BMT and EQ-5D-3L) were administered on screening and days 42, 100, 180, and 365 post-transplant. SETTING: Twenty-eight international academic centers. PATIENTS: Among 108 patients undergoing allo-HSCT, 75 (69%) who completed HRQL surveys at screening and on at least one follow-up visit were included. Baseline characteristics were similar between arms, with a mean age of 36, 59% male, 41% non-white, and 77% intermediate/high disease risk. Most common diagnoses were AML (45%) and ALL (35%). INTERVENTIONS: Myeloablative allo-HSCT with omidubicel or UCB followed by standard GVHD prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. OUTCOMES: This is a secondary exploratory analysis evaluating changes in FACT-BMT and EQ-5D-3L post-transplant, measuring physical, functional, emotional, family/social, and overall well-being. HRQL scores over the first 365 days were compared using the area under the curve (AUC) of mean HRQL trajectories in each arm. RESULTS: Baseline HRQL scores were similar between the two arms. Initial HRQL declines at day 42 were numerically better with omidubicel. Over the first year, AUC of physical well-being scores was better with omidubicel (p = 0.02, mean difference 1.5-3.1), exceeding the minimal clinically important difference (MCID) of 2 points on days 180 and 365. Similarly, AUCs of HSCT-specific and functional well-being scores favored omidubicel (p = 0.04). AUCs of total FACT-BMT scores were better with omidubicel (p = 0.01, mean difference 7.2-11), exceeding the MCID of 7 points at all time points. There were numerical but non-significant improvements in AUCs of FACT-BMT social/family, emotional, and EQ-5D-3L general well-being scores with omidubicel. CONCLUSIONS: Omidubicel showed clinically meaningful and sustained improvements in physical, functional, and overall well-being compared to UCB transplantation.