Key Points Question Does treatment of moderately severe to severe nonproliferative diabetic retinopathy (NPDR) with intravitreal aflibercept injections result in 2-step or greater improvement on the Diabetic Retinopathy Severity Scale in more eyes, fewer vision-threatening complications, and fewer center-involved diabetic macular edema events from baseline through 100 weeks compared with sham injections? Findings In this randomized clinical trial of 402 patients with moderately severe to severe NPDR without diabetic macular edema, more eyes treated with intravitreal aflibercept injections showed a 2-step or greater improvement on the Diabetic Retinopathy Severity Scale at 24, 52, and 100 weeks, with significantly fewer vision-threatening complications and center-involved diabetic macular edema events. No differences in mean change in best-corrected visual acuity at weeks 52 and 100 were observed. Meaning In this study, anatomic improvement was more likely to occur in eyes with moderately severe to severe NPDR that were treated with intravitreal aflibercept injections; in year 2, fixed dosing appeared necessary to maintain anatomic benefit.