The impact of the direction of HLA mismatch (MM) on outcome in unrelated cord blood (UCB) transplantation has not yet been clarified. We conducted a retrospective study using national registry data on 2977 patients who underwent transplantation using a single UCB for leukemia or myelodysplastic syndrome. HLA matching was assessed by serologic data for HLA-A, -B, and -DR loci. The median age of the recipients at transplantation was 41 years (range, 0-82 years), and 2300 recipients (77%) were age >= 16 years. The 2-year overall survival rate was 0.46. The presence of MM only in the graft-versus-host direction or only in the host-versus-graft direction was not associated with overall mortality (hazard ratio [HR], 0.88; P = .317 and HR, 0.95; P = .670, respectively) compared with 1 bidirectional MM. This finding was consistent in both the child and adult cohorts. The presence of MM only in the graft-versus-host direction was associated with a lower incidence of nonrelapse mortality (HR, 0.65; P = .040), significant only in the child cohort. No MM category was associated with relapse. Our findings suggest that the direction of HLA MM does not have a significant impact on overall survival after UCB transplantation. (C) 2013 American Society for Blood and Marrow Transplantation.