Aim: The purpose of this study is to see if switching from intravitreal Ranibizumab, an anti–Vascular Endothelial Growth Factor (anti-VEGF), to Aflibercept is evidence-based in the diabetic Saudi population. We compared the efficacy of three injections of the Aflibercept treatment regimen in diabetic macular edema (DME) cases refractory to Ranibizumab. Methods: In 2018, a retrospective single-arm cohort study was carried out. Cases of refractory DME were evaluated before and after three injections of Ranibizumab, as well as three Aflibercept treatment regimens. Optical Coherence Tomography (OCT) was used to investigate changes in Central Macular Thickness (CMT) (anatomic outcome). In addition, changes in the CMT and Best Corrected Visual Acuity (BCVA) (functional outcome) were assessed. Results: The cohort consisted of 74 eyes from 74 DME patients. As an anatomical indicator, the mean CMT decreased from 482±153 μ to 385.6±134.6 μ after three injections of Ranibizumab. In contrast, with Aflibercept treatment, the mean CMT decreased to 370.2±116.9 μ. The decrease in CMT was statistically significant [94.6μ (95% confidence interval (CI): 54.8; 134.3] (P 0.001). In addition, BCVA improved by two or more lines in 17 (23%) of the eyes treated with Aflibercept, remained unchanged in 40 (54%) of the eyes, and decreased in 17 (23%) of the eyes. Conclusion: The anatomic successes of both anti-VEGF (Ranibizumab and Aflibercept) treatment regimens in Saudi patients with DME are promising. The Aflibercept treatment regimen improves success in refractory DME cases, but the visual improvement appears to be limited.