Purpose. The aim was to evaluate the efficacy of aflibercept in patients with diabetic macular edema (DME) unresponsive to prior anti-VEGF therapy. Methods. Retrospective review of DME unresponsive to previous anti-VEGF switched to aflibercept with 3 months of follow-up. Changes in best correct visual acuity (BCVA), central retinal thickness (CRT), and frequency of injections were analyzed. The percentage of subjects who had ≥20/40 (logMAR equivalent 0.3) and ≤20/200 (logMAR equivalent 1) was evaluated. Results. A total of 32 eyes from 26 patients were included. Mean age was 65 ± 10 years old. The mean number of previous anti-VEGF injections was 5.34 ± 2.38, and the mean number of aflibercept injections at the end of the study was 2.00 ± 0.00. The CRT at baseline was 501.47 ± 150.51 μm and 367.97 ± 124.61 μm at 3 months of follow-up (P < 0.001). The logMAR BCVA at baseline was 0.71 ± 0.36 and 0.65 ± 0.33 at the end of the follow-up (P = 0.037). At baseline, 12.5% of patients had ≥20/40 compared with 25% at the end of follow-up. At baseline, 28.13% of patients had 20/200 or inferior vision compared with 15.63% at the end of the follow-up. Conclusions. DME patients unresponsive to previous multiple ranibizumab injections demonstrate a significant anatomical and functional improvement with the switch to aflibercept.