Background: Patients undergoing hematopoietic stem cell transplantation (HCT) experience a steep deterioration in quality of life (QOL) and mood during hospitalization for HCT. The impact of this deterioration on patients’ long-term QOL and post-traumatic stress disorder (PTSD) symptoms is unknown. Methods: We conducted a prospective longitudinal study of patients hospitalized for HCT. At baseline (day-6), day+1, day+8, and 6 months post-HCT, we assessed QOL (Functional Assessment of Cancer Therapy-Bone Marrow Transplantation [FACT-BMT]) and mood (Hospital Anxiety and Depression Scale [HADS]). We used the PTSD Checklist to assess for PTSD symptoms at 6 months. We used multivariable linear regression models to identify predictors of QOL and PTSD symptoms at 6 months post-HCT. Results: We enrolled 97% (90/93) of consecutively eligible patients undergoing autologous (n = 30), myeloablative allogeneic (n = 30), or reduced intensity allogeneic (n = 30) HCT. Overall, patients’ QOL at 6 months (mean FACT-BMT: 110, 95%CI [104-116]) recovered to baseline pre-transplant values (mean FACT-BMT: 110, 95% CI [107-115]). At 6 months, 28.4% of participants met provisional diagnostic criteria for PTSD, and 43.3% had clinically significant depression. In multivariable regression analyses adjusting for baseline QOL, mood, other covariates, change in QOL and depression scores during hospitalization for HCT predicted impaired QOL (DQOL β = 1.13, P < 0.0001, D HADS-depression β = 2.51, P = 0.001) and PTSD symptoms (DQOL β = 0.50, P < 0.0001, DHADS-depression β = 1.22, P < 0.0001) at 6 months post-HCT. Conclusions: While patients’ overall QOL at 6 months post-HCT returned to baseline values, a significant proportion met provisional diagnostic criteria for PTSD and depression. The decline in QOL and increase in depressive symptoms during hospitalization for HCT were the most important predictors of long-term QOL impairment and PTSD symptoms. Future studies should evaluate whether interventions to improve QOL and reduce psychological distress during HCT may improve long-term QOL and reduce the risk of PTSD symptoms.