PurposeTo investigate the predictors of early diabetic retinopathy (DR) improvement in the RIDE/RISE (NCT00473382/NCT00473330) clinical trials.Patients and MethodsIn RIDE/RISE, adult patients with vision loss due to diabetic macular edema (DME) were randomized to monthly intravitreal ranibizumab 0.3 or 0.5 mg (n=502 total) or sham (n=257). DR severity was graded (using the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale). In this post hoc analysis of RIDE/RISE, eyes with baseline DR score ≥35 were evaluated for ≥2-step improvements, and eyes with baseline DR score ≥43 were evaluated for ≥3-step improvements. The characteristics associated with ≥2- or ≥3-step DR improvement at months 3 or 6 were assessed using univariate and/or multivariable analyses.ResultsThe percentage of eyes with a ≥2- or ≥3-step DR improvement was 20.1% and 3.7% at month 3 and 31.2% and 5.8% at month 6. Odds of ≥2-step DR improvement at months 3 or 6 were significantly greater in eyes with moderately severe to severe nonproliferative DR (NPDR) at baseline versus less severe or more severe DR (both P<0.0001). At month 6, odds of ≥2-step DR improvement were significantly greater in eyes with no DME at month 3 (P=0.008). Most patients with ≥3-step DR improvement at months 3 or 6 had proliferative DR (PDR) at baseline (83.3% and 66.7%).ConclusionThe strongest predictors of DR response to ranibizumab at month 6 were baseline DR severity and DME quiescence at month 3. Eyes with the most robust early improvements had moderately severe or severe NPDR or PDR at baseline.