Fluocinolone acetonide (FAc) is an intravitreal corticosteroid implant approved for the second-line treatment of diabetic macular edema (DME). This study compared outcomes of patients with DME switched directly to an FAc implant, versus indirectly via dexamethasone, after anti-VEGF therapy failure. This is a retrospective, single-center chart review. Patients were assigned to Group A (switched to FAc after anti-VEGF) or Group B (switched to dexamethasone and then to FAc after > 4 months). Charts were reviewed for best-corrected visual acuity (BCVA), central macular thickness (CMT), intraocular pressure (IOP) and cataract development. Forty-nine eyes were included. BCVA increased and CMT decreased with anti-VEGF (both groups), and dexamethasone (Group B only), but regressed after stopping treatment. With FAc, BCVA increased rapidly and significantly: increases were maintained up to 36 months (P < 0.001), except at 18 and 9 months in Groups A and B, respectively. Significant CMT reductions (P < 0.001) were evident after 3 months and maintained up to 36 months in both groups. IOP increase > 21 mmHg occurred in 14 patients (nine in Group A, five in Group B): all were sufficiently treated with IOP-lowering drops. Nineteen phakic eyes (73.1%) developed cataract: seven underwent phaco-emulsification (two in Group A, five in Group B). Similar functional and anatomical improvements occurred in FAc-treated eyes, regardless of whether they first received dexamethasone or switched directly to FAc after anti-VEGF. Safety signals were consistent with corticosteroid class effects. Early switch to FAc could benefit patients who respond insufficiently to anti-VEGF.