Background. Different graft-versus-host disease prophylaxis have been proposed in the setting of reduced intensity and non-myeloablative allogeneic stem cell transplantation. An alternative combination with Sirolimus and Tacrolimus has recently been tested although comparative studies in front of the classical combination with a Calcineurin-inhibitor and Mycophenolate Mofetil or Methotrexate, are lacking. Design and Methods. We describe the results of a prospective multicenter trial using Sirolimus-Tacrolimus as immunoprophylaxis, and compare this approach with our previous experience using Cyclosporine-Mycophenolate in the unrelated donor transplant setting after reduced-intensity conditioning. Results. Forty-five patients received Cyclosporine-Mycophenolate between 2002 and mid-2007, while the subsequent 50 patients receiving transplants from late-2007 received Sirolimus-Tacrolimus. No significant differences were observed either in terms of hematopoietic recovery or acute graft versus host disease, although gastrointestinal aute graft versus host disease ≥2 was more common in the Cyclosporine-Mycophenolate group (55 vs. 21%, respectively, p=0.003). The 1-year cumulative incidence of chronic graft versus host disease was 50% versus 90% for Sirolimus versus Cyclosporine- based regimen, respectively (p<0.001), while the incidence of the extensive chronic disease was 27% versus 49%, respectively (p=0.043). Two-year non-relapse mortality was 18% versus 38% for patients receiving Sirolimus versus Cyclosporine- based regimen, respectively (p=0.02). The event-free survival and overall survival at 2 years were 53% versus 29% (p=0.028) and 70% versus 45% (p=0.018) among patients receiving Sirolimus versus Cyclosporine- based regimen, respectively. Conclusions. In the setting of reduced intensity transplantation from unrelated donor, promising results can be achieved with the combination of Sirolimus-Tacrolimus, due to a lower risk of chronic Graft versus host disease and non-relapse mortality, which translates into better event-free and overall survival, in comparison with Cyclosporine-Mycophenolate. This trial was registered at www.clinicaltrials.gov as 2007-006416-32 by GEL-TAMO/GETH.