We report a retrospective analysis of 128 consecutive patients with high-risk myelodysplastic syndrome (MDS) and AML who received an alemtuzumab-based reduced-intensity conditioning hematopoietic SCT (RIC HSCT). The median recipient age was 53 years (range 21-72 years). A total of 49 (38%) recipients had a sibling donor and 79 (62%) had a volunteer-unrelated donor. The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was assigned to all patients with a score of 0 in 40 (31%), of 1-2 in 45 (35%) and >or=3 in 43 (34%) patients. The 3-year non-relapse mortality (NRM) was 31%, disease-free survival (DFS) was 41% and overall survival (OS) was 46%. The 3-year NRM for patients with a HCT-CI score of 0, 1-2 or >or=3 was 16, 24 and 42%, respectively. The 3-year DFS and OS by HCT-CI was 58 and 69% (score 0), 39 and 39% (score 1-2) and 24 and 32% (score >or=3), respectively. On multivariate analysis, HCT-CI was an independent variable affecting 3-year NRM, DFS and OS (P-value=0.04, 0.01 and <0.01, respectively). Although the disease stage at the time of transplant was an additional independent predictive variable on transplant outcomes, recipient age (>or<50 years) did not have a significant predictive impact. In MDS or AML patients with advanced disease receiving alemtuzumab-based RIC HSCT, the HCT-CI provides an important means of stratifying patients with a high risk of inferior transplant outcomes.