Purpose: To establish the predictive value of specific optical coherence tomography retinal features on visual outcomes and retinal thickness during anti-vascular endothelial growth factor treatment in patients with diabetic macular edema. Methods: Post hoc analysis of compound data of a prospective, 6-month, multicenter, randomized controlled trial of 119 patients with diabetic macular edema receiving either intravitreal bevacizumab or ranibizumab were analyzed to assess the associations between baseline retinal morphologic parameters and change in best-corrected visual acuity and central subfield thickness. Based on the study protocol of the core study, best-corrected visual acuity and central subfield thickness were obtained before each mandatory monthly injection during 6 months. Results: The presence of serous retinal detachment at baseline was associated with significant improvement in best-corrected visual acuity letter score at Month 3 and Month 6 (P < 0.001 and P = 0.01, respectively). In addition, the presence of disorganization of retinal inner layers was associated with lower best-corrected visual acuity letter score at Month 3 and Month 6 (P < 0.05 and P = 0.01, respectively). Conclusion: This study found that serous retinal detachment and disorganization of retinal inner layers were associated with different treatment responses to anti-vascular endothelial growth factor therapy in patients with diabetic macular edema.