Little information is available regarding the effect of the conditioning regimen on the outcome of bone marrow transplantation (BMT) from an unrelated donor. Therefore, we retrospectively compared the outcome after a cyclophosphamide/total body irradiation (Cy-TBI) regimen, an intensified Cy-TBI regimen (Cy-TBI+), a busulfan and cyclophosphamide (Bu-Cy) regimen, and a Bu-Cy regimen with total lymphoid irradiation (Bu-Cy-TLI). Clinical data of 1875 adult patients who underwent unmanipulated unrelated BMT for leukemia or myelodysplastic syndrome by using 1 of the 4 regimens between 1993 and 2002 were extracted from the database of the Japan Marrow Donor Program. The effect of the conditioning regimen was adjusted for other independent significant factors by multivariate analyses. The Cy-TBI regimen was significantly better than the Bu-Cy regimen with regard to the incidence of engraftment failure (odds ratio, 2.49; P = .046) and overall survival (relative risk [RR], 1.31; P = .050). The Bu-Cy-TLI regimen decreased relapse (RR, 0.13; P = .039) but increased nonrelapse mortality (RR, 1.89; P = .0061). The Cy-TBI+ regimen resulted in increased nonrelapse mortality (RR, 1.48; P = .0003) and inferior survival (RR, 1.45; P < .0001). The results of this retrospective study suggested that the Cy-TBI regimen was superior to other regimens in unrelated BMT.