As success of reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) relies primarily on graft-versus-leukemia (GVL) activity, increased minor HLA disparity in unrelated compared to related donors could have a significant impact on transplant outcomes. To assess whether use of unrelated donors (URD) engenders more potent GVL in RIC HSCT compared to matched related donors (MRD), we retrospectively studied 433 consecutive T-replete 6/6 HLA matched URD (n = 246) and MRD (n = 187) RIC HSCT for hematologic malignancies at our institution. Diseases included: acute myelogenous leukemia (AML) (127), non-Hodgkin lymphoma (NHL) (71), chronic lymphocytic leukemia (CLL) (68), myelodysplastic syndrome (MDS) (64), Hodgkin disease (HD) (40), chronic myeloid leukemia (CML) (25), multiple myeloma (MM) (23), myeloproliferative disorder (MPD) (12), acute lymphoblastic leukemia (ALL) (7), and other leukemia (1). All received uniform fludarabine and intravenous busulfan conditioning, and GVHD prophylaxis with tacrolimus/mini-methroxate (mini-MTX) or tacrolimus/sirolimus ± mini-MTX. Unrelated donors were younger compared to MRD (median donor age: 33 years versus 52 years, P < .0001), and provided larger CD34(+) products (median CD34(+) cells infused: 8.7 × 10(6)/kg versus 7.5 × 10(6)/kg, P = .002). Distribution of diseases, disease risk, prior transplant, and cytomegalovirus (CMV) status was similar in both cohorts. Cumulative incidence of grade II-IV acute GVHD (at day +180), 2-year chronic GVHD, and 2-year nonrelapse mortality (NRM) were 20% versus 16%, 55% versus 50%, and 8% versus 6% in URD and MRD, respectively (P = NS). Cumulative incidence of relapse at 2 years was lower in URD, 52% versus 65% (P = .005). With median follow-up of 26.5 and 35.8 months, 2-year progression-free survival (PFS) was significantly better in unrelated donor transplants, 39.5% for URD, and 29% for MRD (P = .01). Overall survival (OS) at 2 years were 56% for URD versus 50% for MRD (P = .53). In multivariable analysis, URD was associated with a lower risk of relapse (hazard ratio [HR] 0.67, P = .002) and superior PFS (HR 0.69, P = .002). These results suggest that URD is associated with greater GVL activity than MRD, and could have practice changing impact on future donor selection in RIC HSCT.