The ß-thalassemias are monogenic blood disorders that can be cured by engrafting hematopoietic stem cells that produce red blood cells containing enough hemoglobin to offset lifelong transfusions. We report here the long-term follow-up (53-83 months) of four adult patients with severe ß-thalassemia major who were infused with autologous CD34+ cells transduced with the TNS9.3.55 globin vector after non-myeloablative conditioning. Peripheral blood and bone marrow gene marking was very stable but low (0.02-0.15 vector copies/diploid genome), nevertheless resulting in reduced transfusion requirements in two patients. Moderate, sub-clinical clonal expansions were associated with vector integration in proximity to cancer-related genes, consistent with non-erythroid activity of globin vectors in stem/progenitor cells. Altogether, our findings identify a minimum baseline for therapeutic genetic modification of long-term repopulating cells, support the sufficiency of non-myeloablative conditioning to achieve stable stem cell engraftment and highlight the need to continuously monitor integration sites of globin vectors and hematopoietic clonality.