Background: The quality of life (QOL) of hematopoietic stem cell transplantation (HCT) patients and their caregivers declines steeply with worsening depression during the first 8 days following stem cell infusion (SCI). In view of this, unique opportunities to develop programs in the confined environment of a Hospital Hospitality House (HHH) to prevent the observed decrease in the QOL and address the depression of the patients and caregivers exist. Methods: We conducted a longitudinal pilot study to collect preliminary data on the impact of post-HCT living arrangements on the quality of life and mood of HCT patients and their caregivers. Patients scheduled to undergo a HCT and their caregivers completed research QOL questionnaires at the following time points: 15 days prior SCI, and 1 day, 8 days, and 30 days post-SCI. The pre-defined primary endpoint was differences in overall QOL of patients and their caregivers staying at a HHH vs. hotel at day 30, as measured by LASA. Results: A total of 44 patients and 44 caregivers were enrolled in this study from Jul 2016-Jan 2017. Day 1 post SCI QOL was worse in the HHH patients (mean = 46.9 vs. 67.6, p = 0.0069). Patients who stayed at HHH were older (63.2 vs. 55.4, p = 0.0279). A multivariate analysis showed that the time point of questionnaire administration had the greatest effect on the overall QOL of patients, with day 8 post HCT showing the most significant worsening in QOL of patients (~20 points, p = 0.0006). A review of data from the entire cohort of patients revealed older patients ( > 60) reported a significantly lower QOL at day 30 post HCT (mean 51.6 vs. 75.3, p = 0.0170) and lower QOL at other time points. Conclusions: Age, type of HCT and baseline QOL significantly influence patients’ QOL following SCT, accounting for the observed worse QOL of patients in the HHH subset. Staying at an HHH improved caregivers’ emotional QOL. Pre-transplant QOL screening is likely to identify patients at risk of significant worsening of QOL post SCT. Evaluation of interventions directed at older patients and patients with low baseline QOL, delivered at the control environment of HHH are worth pursuing.