Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by availability of HLA-matched sibling donors (MSDs). The alternative use of unrelated donors (UDs) is currently challenged by haploidentical-related donors (HRDs). We retrospectively analyzed 209 consecutive patients younger than 60 years undergoing allo-HSCT from UDs (n = 128) or HRDs (n = 81). Cumulative incidences of grade 3-4 acute (17 vs. 2%, p = 0.003) and 2-year moderate and severe chronic (20 vs. 2%, p < 0.001) GVHD were significantly higher with UD. Progression-free survival (PFS) was significantly better with HRD (51 vs. 69%, p = 0.019), without significant difference in the cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and overall survival (OS). Multivariate analyses confirmed the lower risk of acute and chronic GVHD (grade 2-4, HR = 0.43, p = 0.005; grade 3-4, HR = 0.20, p = 0.017; all grades, HR = 0.43, p = 0.012; moderate or severe, HR = 0.12, p = 0.004), better PFS (HR = 0.61, p = 0.046), and GRFS (HR = 0.47, p = 0.001) with HRD. This was confirmed in match-paired analysis. In the absence of MSDs, HRD could be considered as a suitable alternative for patients younger than 60 years.