Purpose: To determine the effect of pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling for diabetic macular edema (DME) compared to anti-vascular endothelial growth factor (VEGF) intravitreal injection (IVI). Methods: This was a retrospective study. We included 260 eyes of 207 patients with DME (central macular thickness (CMT). 250 ƒÊm). 130 eyes underwent PPV with ILM peeling (PPV group) and 130 eyes received anti-VEGF IVI (IVI group) alone. Fluorescence angiography (FLA) was performed in all patients before starting treatment. The best-corrected visual acuity (BCVA) and spectral domain optical coherence tomography (SD-OCT) were investigated preoperatively and at 1, 3, 6 and 12 months postoperatively. Results: The mean BCVA increase was log of the Minimum Angle of Resolution (logMAR) 0.37 ± 0.67 in the PPV group (p < 0.001) and logMAR 0.07 ± 0.30 in the IVI group (p = 0.029) at 12th month follow up. The mean reduction in CMT was 93 ± 216 ìm in the PPV group (p < 0.001) and 70 ± 167 ìm in the IVI group (p < 0.001). Conclusion: Vitrectomy with ILM peeling is a single procedure which results in CMT reduction and leads to clinically significant improvement in BCVA comparable to repeated IVI of anti-VEGF. Preoperative SD-OCT and FLA assessment are essential. Anatomy reconstruction is possible following PPV with ILM peeling.