•Outcomes of 93 adult patients with FLT3-negative AML/MDS who received post-alloHCT AZA maintenance were compared to 357 patients who received no maintenance.•Three-year incidence of progression was 29% versus 33% in the AZA and control groups, respectively (P = .09).•A protective effect of AZA on progression was observed in high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8, P = .009). Maintenance after allogeneic hematopoietic cell transplantation (alloHCT) with hypomethylating agents has yielded conflicting results. We conducted a single center retrospective matched-control analysis with the study group (5-azacitidine AZA group) including adults with FLT3-negative acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received post-transplant AZA maintenance off clinical trial (n = 93). A matched control group was comprised of contemporaneous AML/MDS patients who did not receive any maintenance (n = 357). Primary endpoint was disease progression. The AZA and control groups had comparable patient and disease characteristics except for older age (median: 61 vs. 57 years, P = .01) and lower hematopoietic comorbidity index (median: 2 vs. 3, P = .04) in the AZA group. The 3-year cumulative incidence of progression in the AZA and control groups was 29% vs. 33% (P = .09). The protective effect of AZA on progression was limited to patients with high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8, P = .009). This led to improved progression-free survival both in high-risk AML and MDS patients with maintenance (HR = 0.2, 95% CI = 0.1-0.6, P = .004 and HR = 0.4, 95% CI = 0.2-0.9, P = .04). AZA maintenance was associated with a lower progression rate in patients with high-risk FLT3-negative AML or MDS, and AZA maintenance should be considered for post-alloHCT maintenance in this subset. Outcomes of 93 adult patients with FLT3-negative AML/MDS who received post-alloHCT AZA maintenance were compared to 357 patients who received no maintenance. Three-year incidence of progression was 29% versus 33% in the AZA and control groups, respectively (P = .09). A protective effect of AZA on progression was observed in high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8, P = .009).