To clarify the impact of graft-versus-host disease (GVHD) on the outcome of reduced-intensity stem cell transplantation (RIST), 40 patients who received RIST were compared with those who received conventional stem cell transplantation (CST). RIST regimens consisted of either cladribine (0.11 mg/kg/d x 6, n = 13) or fludarabine (30 mg/m(2)/d x 6, n = 27) with busulphan (BU, 4 mg/kg/d orally x 2), with or without antithymocyte globulin (ATG). CST regimens were either cyclophosphamide/total body irradiation (CY/TBI, n = 23), BU/CY (n = 19) or others (n = 6). The RIST group contained more patients who were at high risk of transplant-related mortality, including older patients, while the two groups contained the same percentages of patients at high risk of relapse. There were no differences between these groups in the incidences of acute (grade II-IV, 31.6% RIST vs 33.3% CST, P = 0.6742) and chronic GVHD (56.2%vs 64.1%, P = 0.8512), relapse rate (15.0%vs 18.8%, P = 0.6642), or overall (69.3%vs 65.6%, P = 0.4817) and progression-free survival (64.7%vs 63.8%, P = 0.6920) at d 500. Multivariate analysis of progression-free survival identified only grade III-IV acute GVHD and relapse risk dose as adverse risk factors. Although GVHD is a major threat in RIST, appropriate induction of GVHD may be associated with anti-tumour activity in RIST comparable to that of CST.