Objective: The aim of this paper is to compare intravitreous aflibercept versus dexamethasone implant followed by aflibercept (sequential treatment group) in patients with diabetic macular edema (DME). Methods: We conducted an observational retrospective study in naïve DME patients, 15 treated only with aflibercept (a monthly injection for the first 5 consecutive doses, followed by an injection every 2 months), and 15 treated with a single dexamethasone implant followed by bimonthly aflibercept. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and qualitative features as well as adverse events were assessed at baseline and at 2, 6, and 12 months. Results: BCVA increased from 70.8 ± 4.1 to 83.5 ± 2.7 letters with aflibercept and from 75.6 ± 2.7 to 86.5 ± 2.5 with sequential treatment (p = 0.551). CMT decreased from 411 ± 26.1 to 288.1 ± 10.5 with aflibercept and from 411.4 ± 24.3 to 260.8 ± 17.9 in the sequential treatment group. The differences between the 2 groups, in terms of visual gain and decreased MT, were not statistically significant (p > 0.05). Nine and 6 injections and 9 and 7 monitoring visits were performed. Conclusion: Sequential treatment in DME, starting with dexamethasone and followed by aflibercept, is a promising alternative that can reduce the treatment burden in the first year without statistically significant differences in terms of visual gain and decreased MT compared to aflibercept only.