<p>Beta-thalassemia major (TM) is associated with a high incidence of thromboembolic events and prothrombotic changes, suggesting a chronic hypercoagulable state. Hematopoietic derived endothelial progenitor cells (hEPCs), derived from the bone marrow, contribute to vascular repair, and their quantity and function inversely correlate with thrombotic risk. In this study, we aimed to evaluate the number and colony-forming capacity of hEPCs in adult patients with TM. hEPCs were isolated from peripheral blood mononuclear cells of TM patients and healthy controls. Flow cytometry was used to measure the proportion of mononuclear cells co-expressing VEGFR-2 and CD34 or CD133. hEPCs were cultured for 7 days, after which colony-forming capacity and viability were assessed via microscopy and MTT assay. TM patients (<i>n</i> = 25) had a significantly lower proportion of VEGFR-2⁺CD34⁺ cells compared to controls (<i>n</i> = 11); 0.95% (0.36–1.65%) vs. 1.78% (1.1–4.2%), <i>p</i> = 0.02. hEPC colony counts and viability were also reduced: 0 (0–0.5) vs. 3 (2–4), and 0.02AU (0.01–0.05) vs. 0.2AU (0.18–0.23), respectively (both <i>p</i> &lt; 0.0001). Subgroup analyses suggested lower VEGFR-2⁺CD34⁺ proportions in patients with prior thrombosis (<i>n</i> = 6) and in splenectomized patients (<i>n</i> = 21). Patients with TM exhibit reduced hEPC numbers and impaired colony-forming capacity, which may be associated with the hypercoagulable state observed in this population.</p>