Background/Purpose: This study compared the effects of three induction doses of anti-vascular endothelial growth factor (anti-VEGF) on diabetic macular edema (DME) with that of long-term treatment using biomarkers to find out the predictability potential of early response to anti-VEGF treatment for the long-term restorative effect. Methods: We retrospectively reviewed the clinical and optical coherence tomography (OCT) data of 71 DME eyes treated with three monthly anti-VEGF doses and followed for 1 year. BCVA, central subfield thickness (CST), subretinal fluid (SRF), intraretinal cysts, hyperreflective foci (HF), disorganization of inner retinal layers (DRILs), ellipsoid zone/external limiting membrane (EZ/ELM) integrity, and vitreoretinal relationships were assessed at baseline, 3, 6, and 12 months. Results: Patients (50.7% male) had a mean follow-up of 12 months. After three anti-VEGF doses, 19 eyes required no additional injections, 25 continued anti-VEGF, 20 switched to dexamethasone implants, and seven received combination therapy. Best corrected visual acuity (BCVA) improved from 0.52 to 0.40 logMAR at 3 months, 0.30 at 6 months, and stabilized at 0.40 at 12 months. CST decreased from 406 µm to 317 µm at 3 months and 307 µm at 12 months. Significant early improvements in BCVA, CST, SRF, and intraretinal cysts were sustained in the long-term follow-up. HF reduction became significant after 6 months, while DRIL and EZ/ELM integrity remained unchanged. Conclusions: The improvement of OCT biomarkers in DME patients supported that intravitreal anti-VEGF significantly restored the retinal microstructure, which was already evident at 3 months in the control after anti-VEGF induction.