Background: Diabetes mellitus (DM) is characterized by an atypical activation of immune cells, leading to the onset and progression of chronic inflammation and atherosclerosis. This condition, named “trained immunity”, appears to initiate in hematopoietic stem/progenitor cells (HSPCs). Nowadays, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a hot topic of investigation for their anti-inflammatory and immunological properties. We previously demonstrated that HSPCs express the GLP-1R whose stimulation with liraglutide (LIRA) prevents oxidative stress and functional impairment induced by hyperglycemic status (HG). Aim: To assess whether LIRA treatment can also avert HG-induced senescence and proinflammatory myeloid differentiation of HSPCs. Methods: Cord blood-derived CD34+ HSPCs of healthy donors were expanded in normal-glucose (NG; with 30 mM mannitol as osmotic control) or high-glucose (HG; 30 mM) and treated or not with LIRA (100nM) in serum-free medium plus cytokines (FLT3, SCF, IL3 and IL6) for up to 20 days. The expression of p21, p27, IL6, TNFα and NFkB-p65 genes was assessed by qPCR. ROS production and CD34+ HSPC-derived monocyte subsets were assessed by flow cytometry, while cytokine secretion after LPS stimulation was measured by ELISA assay. Results: LIRA treatment showed a significant impairment of CD34+ HSPC proliferation and the upregulation of senescence-associated secretory phenotype (SASP) genes such as p21, p27, NFkB-p65, IL6 and TNFα promoted by HG exposure (p≤0.05). Moreover, it was observed a notable reduction in HG-induced ROS production treated with LIRA. The analysis of HSPC myeloid differentiation in vitro revealed that HG-CD34+ produced inflammatory and highly reactive intermediate (CD14+CD16+) monocyte subpopulation, characterized by higher LPS-induced release of IL6 and TNFα. The LIRA treatment significantly reduced the accumulation of intermediate monocytes and their inflammatory phenotype (p≤0.05). Conclusions: These results show that GLP1R agonists have immunomodulatory properties that could be useful in developing new treatments for immune system dysregulation in diabetes.