Purpose Signal peptide-CUB-Epidermal growth factor-like domain-containing protein 1 (SCUBE-1) is a protein expressed on the cell surface of endothelial cells and platelets. We aimed to determine the alterations in SCUBE-1 levels in patients at different stages of diabetic retinopathy (DR). Materials and methods Participants were grouped into 4 regarding the presence and stage of diabetic retinopathy as follows: control group (n 32), patients without DR (n 39), patients with background DR (n 42) and patients with proliferative DR (n 55). Age, gender, duration of diabetes, fasting blood glucose levels, serum hemoglobin A1c (HbA1c), SCUBE-1 and malondialdehyde (MDA) levels of the patients were recorded. Central macular thickness and central macular volume were recorded and compared between groups. Results Totally 136 patients with diabetes mellitus and 32 control cases were included in the study. There is a significant increase in SCUBE-1 and MDA levels with an advance in DR. In correlation analysis, there was only a significant correlation present between serum SCUBE-1 and MDA levels (p 0.001) but not with other parameters. Conclusion For the first time in literature, we determined a significant increase in SCUBE-1 levels in patients with DR. Moreover, with an advance in DR, SCUBE-1 levels were also increasing.