Purpose: To compare the 6-month anatomic and best-corrected visual acuity (BCVA) response after sustained-release dexamethasone (DEX) intravitreal implant between nonvitrectomized and vitrectomized eyes with persistent diabetic macular edema (DME). Methods: Retrospective, comparative, and consecutive review of the medical records of 58 patients with decreased visual acuity, due to refractory DME, who underwent a single injection of Ozurdex between November 2010 and January 2012, at the Instituto de Microcirurgia Ocular, Barcelona, Spain. Then, we divided patients into 2 groups: 24 eyes who had undergone standard pars plana vitrectomy (vitrectomized group), and 34 eyes that were not operated on (nonvitrectomized group). Outcomes measured were BCVA and foveal thickness (FT) at baseline and at months 1, 3, and 6. Results: Twenty-four of 58 eyes had prior vitrectomy (41%). Statistically significant improvement in BCVA also was seen at 1 month after treatment with a DEX implant and at each subsequent follow-up visit, in either groups (P<0.05). All of the FT reduction outcomes were statistically significant in both groups, with respect to baseline data (P<0.05). There were no statistically significant differences in BCVA and FT between nonvitrectomized and vitrectomized eyes at any time point (P<0.05). Conclusion: In this study, the clinical findings were similar between nonvitrectomized and vitrectomized eyes. Intravitreal treatment with a DEX implant safely reduced DME and improved visual acuity in both groups. No statistically significant differences were found between the 2 groups regarding FT and BCVA.