Aim <p>To quantitatively analyze change in the extent of hard exudates (HEs) following anti-VEGF therapy for diabetic macular edema (DME) and its relationships with visual outcomes.</p> Methods <p>This post-hoc analysis of DRCR Protocol T included 260 eyes of 260 patients. The volume of HEs was measured by automatically quantifying hyper-reflective foci (HRF) on structural optical coherence tomography (OCT) volumes using a supervised convolutional neural network architecture, “DUCK-Net”. HEs were quantified within the entire ETDRS grid as well as within the central subfield (CSF), inner ring (IR), and outer ring (OR) at baseline, 4, 12, 24, and 52 weeks (w) after treatment. The extent of HEs at baseline and over time was then correlated with visual acuity (VA) and retinal thickness outcomes.</p> Results <p>Following initiation of anti-VEGF therapy, HEs significantly increased from baseline (0.0293 ± 0.0455 mm3) to w4 (0.0328 ± 0.0492 mm3) and peaked at w12 (0.0350 ± 0.0513 mm3), but decreased by w52 (0.0165 ± 0.0275mm3) within the entire ETDRS region (P = &lt; 0.001, respectively), as well as within the OR and IR. Multiple regression analysis revealed that baseline HEs within the OR was one of the independent predictors of w52 VA (adjusted R2 = 0.160).</p> Conclusions <p>Following anti-VEGF for DME, HEs initially increase, followed by a subsequent decrease over one year. Greater extent of HEs at baseline is associated with worse visual outcomes at one year.</p>