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 μm to 287 ± 115 and 371 ± 78 μm at 3 months and increased to 460 ± 186 μm and 547 ± 175 μm 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.