SummaryHigh genetic heterogeneity in the human leukocyte antigen (HLA) increases the likelihood of efficient immune response to pathogens and tumours. As measure of HLA diversity, HLA evolutionary divergence (HED) has been shown to predict the response of tumours to immunotherapy and haematopoietic stem cell transplantation (HSCT) in adults. We retrospectively investigated the association of HED with outcomes of 153 paediatric/young adults patients, treated for malignant disorders with HSCT from 9–10/10 HLA‐matched unrelated donors. HED was calculated as pairwise genetic distance between alleles in patient HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1 and ‐DPB1, using the locus median to stratify patients with ‘high’ or ‘low’ HED. Patients with high HED‐B and ‐DRB1 showed significantly improved disease‐free survival (DFS), especially when combined (70.8% vs 53.7% p = 0.008). High HED‐B + ‐DRB1 was also associated with improved overall survival (OS) (82.1 vs 66.4% p = 0.014), and concomitant reduction of non‐relapse‐mortality (5.1% vs 21.1% p = 0.006). The impact on OS and DFS of combined HED‐B + ‐DRB1 was confirmed in multivariate analysis [hazard ratio (HR) 0.39, p = 0.009; and HR 0.45, p = 0.007 respectively]. Only high HED scores for HLA‐DPB1 were associated, in univariate analysis, with reduced incidence of relapse (15.9% vs 31.1%, p = 0.03). These results support HED as prognostic marker in allogeneic HSCT and, if confirmed in larger cohorts, would allow its use to inform clinical risk and potentially influence clinical practice.