Purpose: The aim of this study was to define a new pathogenetic classification of diabetic macular edema (DME) and to present the results of its application in common clinical practice. Methods: One hundred and seventy-seven consecutive patients with center-involving DME, central retinal thickness (CRT) ≥250 μm, were prospectively enrolled. A complete ophthalmological examination included best-corrected visual acuity (BCVA) assessment, fundus photography, and spectral-domain optical coherence tomography (OCT). The DME classification was broken down into 4 categories, combining the presence of retinal thickening with the presence/absence of visible vascular dilations and OCT-detectable macular traction. The OCT parameters included were as follows: CRT, subretinal fluid, intraretinal cysts, and hyperreflective foci (HF). Results: Four subtypes of DME were identified: vasogenic (131 eyes, DME with vascular dilation), nonvasogenic (46 eyes, DME without vascular dilation), tractional (11 eyes), and mixed DME (13 eyes). Vasogenic DME was the pattern mainly represented in each subclass of CRT (< 300, 300-400, and > 400 μm), with tractional DME observed especially with CRT > 400 μm. Internal and external cysts and a greater presence of hard exudates were predominantly found in vasogenic DME, whereas HF was equally distributed in the 4 DME subgroups. Conclusion: The study offers a new pathogenetic classification able to detect significant differences among DME subtypes. A tailored therapeutic approach could take into consideration specific changes associated with the different DME subtypes.