We present the largest prospective real-world experience in 159 patients who received the triple combination of tacrolimus/sirolimus/mycophenolate mofetil after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC-alloHSCT) from matched-related (MRD), matched-unrelated (MUD) or mismatched-unrelated donors (MMURD). Despite the high-risk and elderly population, non-relapse mortality (NRM) at day +100 and 1 year was 5.1% and 8.6%. Grades 2-4 and 3-4 acute Graft-versus-host disease (GvHD) at day +180 was 30.3% and 13%, respectively. Chronic GvHD at 1 and 3 years was 23.2% and 41% and for moderate/severe was 13.2% and 26.6%, respectively. With a median follow-up of 20 months, the 1- and 3-year progression-free survival was 60% and 49%, the GvHD-free relapse-free survival was 44% and 32%, and the overall survival was 70.3% and 61%, respectively, for the entire cohort. Patients receiving allo-HSCT from MMURD showed a higher incidence of aGvHD with impact on survival endpoints. GvHD prophylaxis with the triple-drug combination tacrolimus/sirolimus/mycophenolate mofetil showed excellent results in terms of NRM, GvHD and survival in a high-risk, frail and elderly population in the context of RIC-HSCT from MRD and MUD. The subgroup of patients receiving RIC-HSCT from MMURD might probably benefit from other prophylaxis strategies.