Objectives: Dickkopf-1 (DKK-1) is WNT/b-catenin pathway antagonist which plays a detrimental role in the development of diabetic retinopathy (DR). This research aimed to assess serum DKK-1 levels in diabetic patients who have and have not developed DR and, compare them with the control subjects finding out whether we can use it as an indicator for DR early diagnosis and to find out which one of the widely used two groups of antidiabetic treatments had the greater effect on this biomarker and hence on the progression of DR. Methods: The study participants were divided into two subgroups: First, 70 patients (36 male, 34 female) with type 2 diabetes mellitus, among them 35 patients diagnosed with DR and 35 with no evidence of DR, and secondly, non-diabetic controls (11 male, 9 female) were selected from the patients attending Ibn AL-Haitham hospital for ophthalmology and a specialized center for endocrinology and diabetes. Venous blood samples of all participants were drawn after an overnight fast, and serum samples were stored at -20ºC until DKK-1 assay. Results: Serum DKK-1 showed significantly lower levels in diabetic patients with (6.1 ± 2 ng/mL) or without DR (14 ± 6.2 ng/mL) when compared to those of controls (34 ± 12.25 ng/mL) (p 0.05). Furthermore, serum DKK-1 levels were lower in the late stage of DR compared to the early stage 5.6 ± 1.7 and 7 ± 1.9 ng/mL, respectively. Furthermore, DPP-4 inhibitors cause a better increment in DKK-1 levels when compared to SU in the NDR group. Conclusions: Reduced serum levels of DKK-1 are related to the existence and worsening of DR and have the prospect to serve as an indicator for this condition.