To analyze the morphological characteristics and long-term visual outcomes in eyes with diabetic retinopathy (DR) and diabetic macular edema (DME) treated with anti−vascular endothelial growth factor (anti-VEGF) therapy. Retrospective clinical cohort study. Patients with a long-term follow-up and evidence of resolved DME in at least 1 visit (study visit) after 5 years of follow-up after the initiation of anti-VEGF therapy were included. At the study visit, structural optical coherence tomography (OCT) scans were reviewed for qualitative features reflecting a distress of the neuroretina or retinal pigment epithelium (RPE). A quantitative topographical assessment of the inner and outer retinal thicknesses was also provided. A total of 61 eyes (50 patients) were included and were divided into 2 subgroups according to visual acuity (VA) at the study visit, yielding a group of 24 eyes with a VA <20/40 (“poor/intermediate vision” group), and 37 eyes with a VA ≥20/40 (“good vision” group). The external limiting membrane (ELM) and RPE bands were more frequently disrupted or absent in the poor/intermediate vision group (P = .003 and P = .019). Similarly, disorganization of retinal inner layers was more prevalent in the poor/intermediate vision group (P = .013). The foveal and parafoveal outer retinal thicknesses were reduced in eyes with poor/intermediate vision (P = .022 and P = .044). Multivariate stepwise linear regression analysis demonstrated that VA was associated with appearances of the RPE and ELM (P < .0001 and P = .048), foveal and parafoveal outer retinal thicknesses (P = .046 and P = .035). Modifications in the outer retina and RPE represent OCT biomarkers of long-term visual outcomes in eyes with DME treated with anti-VEGF.