IntroductionCalcium dobesilate (CaD) has been used in the treatment of diabetic retinopathy (DR) due to its potential in protecting against retinal vascular damage. However, there is limited evidence exploring its efficacy in combating DR progression. This study is aimed at evaluating whether CaD could prevent DR progression into an advanced stage among Chinese patients with mild-to-moderate non-proliferative DR (NPDR).Methods and analysisThis study is a single-blind, multicentre, cluster-randomised, controlled superiority trial. A total of 1272 patients with mild-to-moderate NPDR will be enrolled and randomly assigned at a 1:1 ratio into the control group (conventional treatment group) and the intervention group (conventional treatment plus CaD (500mg three times per day) for 12 months). Patients will be followed at 1, 3, 6 and 12 months after randomisation and receiving treatments, with the severity of DR assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. The primary endpoint is the progression of DR during follow-up, which is defined as an increase of two or more steps in the ETDRS scale. The secondary endpoints include the concomitant changes in visual acuity, presence, number, location and type of retinal lesions, and retinal blood vessel diameter as well as the arteriovenous ratio at different visits.Ethics and disseminationEach local ethics committee (first Vote: Ethical Review Committees of Zhongda Hospital of Southeast University (2019ZDSYLL132-P01)) has approved the study. The results will be published in high impact peer-reviewed scientific journals aimed at the general reader.Trial registration numbersNCT04283162.