Aims To evaluate the efficacy and safety of intravitreal dexamethasone implant (DEX-implant) for diabetic macular edema (DME) in real-life practice with an extended follow-up for up to 5 year. Methods This multicentric retrospective study reviewed 227 eyes of 152 patients with DME treated by DEX-implant. Main outcome measures included changes in best corrected visual acuity (BCVA), central macular thickness (CMT), time to retreatment and incidence of adverse effects. Results The mean number of DEX-implant received by patients was 2.6 (+/- 2.2) with a mean (SD) follow-up of 20.1 (+/- 15.8) months, median [IQR] 15.8 [7.4-30.1]. The mean time of retreatment was 6.9 months. The mean maximal BCVA gain during follow-up was 12.3 (+/- 12.7) letters. A gain of >= 5, >= 10 and >= 15 letters from baseline BCVA was obtained for 71.8%, 48.9% and 34.8% of eyes, respectively. A total of 62.6% of eyes presented a significant anatomical response (decrease of CMT >= 20%), and DME was resolved (absence of cystoid macular spaces on OCT) in 37% of cases at the end of the follow-up. A transient increase in intraocular pressure >= 25 mmHg occurred in 14.1% of eyes, and cataract surgery was performed for 49.1% of the phakic eyes during the follow-up. Four eyes developed a proliferative diabetic retinopathy. Conclusion This large cohort study showed favorable long-term outcomes when using DEX-implant, which provides substantial long-term benefits in the treatment of DME in real life.