Purpose: To compare the efficacy and safety of the dexamethasone (DEX) intravitreal implant of vitrectomized and nonvitrectomized eyes in real-world conditions. Methods: This was a retrospective, multicenter, observational study. All consecutive patients presenting with at least one 0.7-mg intravitreal injection of DEX implant were included in this study. A total of 186 eyes in 170 patients were analyzed. Fifty-nine eyes were vitrectomized at baseline and 127 eyes had no vitrectomy at the last visit. Among the baseline-vitrectomized eyes analyzed, 72.9% were treatment naive eyes, and 44.1% of nonvitrectomized eyes had no prior treatment. Results: There was no statistically significant difference in the variation in best-corrected visual acuity (BCVA) between the 2 groups (P = 0.343). Variations of BCVA and central macular thickness were not significantly different between nonvitrectomized eyes and baseline-vitrectomized eyes. The intraocular pressure profile was the same in both nonvitrectomized eyes and baseline-vitrectomized eyes. The mean interval between injections was 6.9 months (2; 27.7) for nonvitrectomized eyes and 5.2 months (4; 22.1) for baseline-vitrectomized eyes (P = 0.001). The mean number of IVIs was 2 (1; 6) for nonvitrectomized eyes and 2.3 (1; 10) for baseline-vitrectomized eyes (P = 0.188) during the total follow-up period. Conclusion: This large cohort shows that vitrectomy does not seem to influence the efficacy and safety profile of dexamethasone intravitreal implant for DME.