PURPOSE: The aim of this study is to assess the effect of repeated injections of dexamethasone implants in patients with persistent diabetic macular edema (DME) despite prior therapies. METHODS: This retrospective interventional study involved 47 DME-afflicted eyes, which were administered $≥$2 intravitreal injections of dexamethasone. Group 1 (34 eyes) received a dexamethasone monotherapy, whereas group 2 (13 eyes) received a combination therapy with intravitreal antivascular endothelial growth factor as needed. The duration of dexamethasone effect until retreatment and the change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were defined as outcome measures. RESULTS: A total of 197 injections of dexamethasone were administered in group 1 and 52 in group 2 during a mean follow-up of 23 $±$ 10 and 24 $±$ 13 months, respectively. Mean time to reinjection was 4.6 $±$ 0.5 (group 1) and 5.3 $±$ 1.0 months (group 2; P = 0.17). Reinjection intervals did not shorten over time for up to 10 dexamethasone injections per eye in group 1 and BCVA improved from before 1 month after the first implantation, 7.0 letters (P = 0.04). In group 2, there was no significant improvement in BCVA at any time point. CRT decreased from 534 $±$ 208 and 529 $±$ 215 $μ$m to 287 $±$ 115 and 371 $±$ 78 $μ$m at 3 months and increased to 460 $±$ 186 $μ$m and 547 $±$ 175 $μ$m before reinjection (groups1 and 2, respectively). The maximal CRT before each implantation remained stable over time. CONCLUSIONS: In eyes with chronic DME that respond incompletely to prior therapy or require frequent reinjections, dexamethasone shows promising long-term anatomic and functional improvement. The absence of a treatment effect reduction over time argues against a relevant rebound phenomenon.