To evaluate the predictive effect of TCED-HFV grading and imaging biomarkers on anti-vascular endothelial growth factor (anti-VEGF) treatment in diabetic macular edema (DME).81 eyes of 81 DME patients who were treated with anti-VEGF were included in this retrospective cohort study. All patients underwent a comprehensive ophthalmic examination at baseline and follow-up, including best-corrected visual acuity (BCVA), fundus photography, and spectral domain-optical coherence tomography (SD-OCT). Baseline imaging biomarkers were qualitatively and quantitatively graded according to the TCED-HFV classification protocol, and DME was divided into early stage, advanced stage, severe stage, and atrophy stage.Six months post treatment, central subfield thickness (CST) in 49 eyes (60.5%) had decreased by 10% from baseline, 30 eyes (37.0%) had achieved CST < 300 μm, and 45 eyes (55.6%) had BCVA improved by more than five letters. Multivariate regression analysis revealed that eyes with baseline CST ≥ 390 μm had a higher probability of ≥ 10% reduction in CST from baseline, and eyes with abundant hyperreflective dots (HRD) had a lower probability of 10% reduction in CST (all P < 0.05). Eyes with vitreomacular traction (VMT) or epiretinal membrane (ERM) at baseline were less likely to reach the end point of CST < 300 μm (P < 0.05). BCVA increases of more than five letters were less likely in eyes with baseline BCVA ≥ 69 letters, complete or partial destruction of ellipsoid zone (EZ) at baseline (all P < 0.05). TCED-HFV staging was negatively correlated with BCVA at both baseline and 6 months (Kendall's tau-b=-0.39 and - 0.55, all P < 0.01). TCED-HFV staging was positively correlated with CST at 6 months (Kendall's tau-b = 0.19, P = 0.049) and negatively correlated with the reduction of CST (Kendall's tau-b=-0.32, P < 0.01).The TCED-HFV grading protocol facilitates a comprehensive assessment of DME severity, standardizes the grading of multiple imaging biomarkers, and predicts the anatomical and functional outcomes of anti-VEGF treatment.© 2023. The Author(s).