Objective: Proliferative diabetic retinopathy (PDR) is characterized by the formation of abnormal new vessels in the retina due to both the self-expansion of vascular endothelium and the contribution of bone marrowderived endothelial progenitor cells (EPC). In line with this evidence, we previously observed that circulating EPC from patients with type 1 diabetes and untreated PDR had a greater clonogenic capacity than EPC from patients with no signs of retinopathy. Whether an abnormal number or function of EPCs also characterize earlier stages of diabetic retinopathy and, consequently, whether EPCs may have a role in the pathogenesis of this complication of diabetes, is presently unknown. Materials and Methods: In type 1 diabetic patients with (A) < 20 years of diabetes with signs of non-proliferative retinopathy (n=19), (B) > 25 years of diabetes without retinopathy (n=20), (C) <5 years of diabetes without retinopathy (n=19) and age-and gender-matched nondiabetic controls (n=17), we measured the number of circulating EPCs (CD45dim, CD34+,VEGFR-2+) by flow cytometry; their clonogenic potential by the Hill’s assay; and plasma concentrations by ELISA of VEGF and SDF-1, the two cytokines known to mobilize EPC. All measurements were performed when plasma glucose levels were between 70 and 200 mg/dl. Results: The clonogenic potential of EPCs was significantly increased in group A when compared to group B (p<0.0007) and to non diabetic controls (p<0.002). Group C did not significantly differ from groups A and B possibly suggesting that, along with time, some of its patients will probably move to group A and some to group B. In contrast, the number of circulating EPCs and the cytokines plasma levels were similar in the four groups. Interestingly, platelet-associated VEGF was significantly increased in group B when compared to groups A (P=0.006) and C (p=0.0005), possibly suggesting a protective role of this parameter on the retina. The differences in clonogenic potential between the diabetic groups were not explained by different glycemic control (blood glucose and HbA1c). Conclusion: Increased clonogenic potential of EPCs characterizes patients with type 1 diabetes and non-proliferative retinopathy. This abnormality is therefore not restricted only to the proliferative stage of this complication, but seems to parallel its development. Whether the increased clonogenic potential of EPCs is directly involved in the pathogenesis of diabetic nephropathy and, consequently, whether the progression of this complication could be controlled by normalizing this abnormality, remains to be investigated by further studies.