T-cell depletion (TCD) and immunosuppressive medications (ISTs) are 2 methods used for graft-versus-host disease (GVHD) prophylaxis in unrelated donor (URD) transplantation. However, comparisons of the clinical outcomes including quality of life and direct medical costs associated with each type of procedure have not been reported. We reviewed 48 TCD and 98 IST procedures performed from 1/1/97 to 12/31/99 at the Dana-Farber Cancer Institute, Boston, MA. With a median follow-up of 1.5 years for survivors, no differences were seen in relapse, acute GVHD, and overall survival between TCD and IST patients. Multivariable Cox modeling showed that age of 50 years or less (P =.002) and low-risk disease (P =.001) predicted survival, but method of GVHD prophylaxis (P =.6) and degree of human leukocyte antigen (HLA) matching (P =.8) did not. A subset of patients (53%) completed quality of life surveys prior to and at 6 and 12 months after transplantation; participation in the quality of life study was not associated with clinical characteristics and outcomes. No differences were seen in quality of life scores prior to transplantation, and changes over time were similar between groups. Costs ($113 000 vs $155 000, P <.0001) and total hospital days (34 vs 46, P =.0006) were significantly lower for patients undergoing TCD procedures. As prospective, randomized studies comparing methods of GVHD prophylaxis are performed, assessment of quality of life and costs should be included to fully understand the overall impact of each intervention.