Seventy-three leukemic HLA-identical siblings undergoing BMT received individualized prophylaxis against GVHD based on estimated risk of GVHD development. Patients with an estimated low risk of GVHD were given MTX. MTX + CsA were given to patients having a high risk of GVHD. CsA treatment was discontinued as early as possible after engraftment followed by weekly MTX until 3 months after BMT. Conditioning was busulfan + CY (BuCY, n = 35) or CY/TBI (n = 38). CY/TBI patients given MTX combined with CsA for 1 year served as retrospective controls (n = 39). The incidence of acute GVHD was similar in the three groups. The incidence of chronic GVHD was 59% in the BuCY group and 40% in the CY/TBI group compared with 25% in the controls (p = 0.002 vs BuCY). The incidence of relapse at 2 years was 6% in the BuCY group and 35% in the CY/TBI group (p = 0.01) vs 36% in the control group (p = 0.01 vs BuCY). Actuarial 2-year relapse-free survival was 76, 58 and 51% in the three groups, respectively (p = 0.06, BuCY vs controls). In multivariate analysis individualized prophylaxis was associated with chronic GVHD. Poor survival correlated with high risk leukemia and absence of chronic GVHD. Poor relapse-free survival was associated with high risk leukemia and TBI.