The hematopoietic cell transplantation specific comorbidity index (HCT-CI) has been developed to identify patients at high risk of mortality after an allograft. Reduced-intensity/non-myeloablative regimens have decreased the non-relapse mortality (NRM) in elderly and/or heavily pretreated patients. We performed a retrospective study to assess whether HCT-CI may predict clinical outcomes in a cohort of 203 patients with non-Hodgkin's (NHL; n=108), Hodgkin's lymphomas (HL; n=26), and multiple myeloma (MM; n=69), who were transplanted from a human leucocyte antigen (HLA)-matched sibling (n=121) or an unrelated donor (n=82) after a reduced-intensity regimen (n=154) or a low-dose total body irradiation-based non-myeloblative regimen (n=49). Cumulative incidence of NRM was 5, 16 and 20% at 1 year and 6, 24 and 27% at 2 years, for patients with an HCT-CI of 0, 1-2 and > or =3, respectively. By multivariate analysis, HCT-CI significantly predicted NRM (hazard ratio (HR)=1.6, P=0.03), overall survival (OS; HR=1.62, P<0.001) and progression-free survival (PFS; HR=1.43, P=0.002). Moreover, the Karnofsky performance status was also significantly associated with OS and NRM (HR=1.62, P<0.001 and HR=2.12, P=0.04, respectively). Conditioning type did not affect outcome after stratifying patients by HCT-CI. In the light of our study, all future prospective trials of the Gruppo Italiano Trapianti di Midollo (GITMO) will include the HCT-CI to stratify patients.