Background: Diabetic macular edema (DME) is currently treated by anti‑vascular endothelial growth factor (anti‑VEGF). Aim: The aim of this study was to evaluate the effect of intravitreal anti‑VEGF in different types of DME classified by optical coherence tomography (OCT). Methods: This retrospective study included 161 treatment‑naive eyes (116 patients) diagnosed with DME in two tertiary medical centers, which were classified into three groups according to initial OCT finding: diffuse retinal thickening (DRT), cystoid macular edema (CME), and serous retinal detachment (SRD). All eyes received three monthly loading doses of anti‑VEGF. Primary and secondary outcomes were the improvement of best‑corrected visual acuity (BCVA) and the decrease of central foveal thickness (CFT) on OCT, respectively. Results: Among the three groups, there was no significant difference in baseline BCVA (P = 0.137); however, the SRD group had the thickest baseline CFT (P < 0.001). After three loading doses of anti‑VEGF, the BCVA of all three groups improved from baseline (DRT vs. CME vs. SRD, P = 0.0002, P < 0.0001, and P < 0.0001, respectively), while the SRD group seemed to have relatively better improvement among three groups although not significant (P = 0.051). The CFTs of all three groups significantly decreased from baseline (P < 0.0001 in all three groups). The CFT decreased the most in the SRD group, followed by the CME group, and the least in the DRT group (P < 0.001). Conclusion: Anti‑VEGF therapy improved the anatomical structure and function in all types of DME; SRD responded the best.