AbstractPurposeRetinal non‐perfusion (RNP) is fundamental to disease onset and progression in diabetic retinopathy (DR). Whether anti‐vascular endothelial growth factor (anti‐VEGF) therapy can modify RNP progression is unclear. This investigation quantified the impact of anti‐VEGF therapy on RNP progression compared with laser or sham at 12 months.MethodsA systematic review and meta‐analysis of randomised controlled trials (RCTs) were performed; Ovid MEDLINE, EMBASE and CENTRAL were searched from inception to 4th March 2022. The change in any continuous measure of RNP at 12 months and 24 months was the primary and secondary outcomes, respectively. Outcomes were reported utilising standardised mean differences (SMD). The Cochrane Risk of Bias Tool version‐2 and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines informed risk of bias and certainty of evidence assessments.ResultsSix RCTs (1296 eyes) and three RCTs (1131 eyes) were included at 12 and 24 months, respectively. Meta‐analysis demonstrated that RNP progression may be slowed with anti‐VEGF therapy compared with laser/sham at 12 months (SMD: −0.17; 95% confidence interval [CI]: −0.29, −0.06; p = 0.003; I² = 0; GRADE rating: LOW) and 24‐months (SMD: −0.21; 95% CI: −0.37, −0.05; p = 0.009; I² = 28%; GRADE rating: LOW). The certainty of evidence was downgraded due to indirectness and due to imprecision.ConclusionAnti‐VEGF treatment may slightly impact the pathophysiologic process of progressive RNP in DR. The dosing regimen and the absence of diabetic macular edema may impact this potential effect. Future trials are needed to increase the precision of the effect and inform the association between RNP progression and clinically important events.PROSPERO RegistrationCRD42022314418.