Objective: To assess the effectiveness and safety of the intravitreal fluocinolone-acetonide implant (FAc-i) in patients with chronic diabetic macular edema who did not sufficiently respond to other available therapies. Methods: This was a multicenter, prospective, non-randomized, and phase-IV observational study conducted on patients with recurrent-DME who were insufficient responders to currently available therapies (REACT-Study). The primary end-point was the mean change in best-corrected-visual-acuity from baseline to month-24 values. Results: Thirty-one eyes from 31 patients were included in the study. Mean age was 68.0 +/- 7.7 years, and 10 (32.3%) were women. Study patients had received 5.3 +/- 7.3 previous DME treatments before starting the study. In the overall study sample, BCVA improved from 56.1 +/- 12.3 letters at baseline to 62.4 +/- 17.0 letters at month-24 (p = 0.0510). The eyes with a baseline BCVA < 70 ETDRS letters had a significant improvement in BCVA from 53.2 +/- 10.2 letters at baseline to 61.5 +/- 17.9 letters at month-24 (p = 0.0165). In the overall study population, central-subfoveal-thickness (CST) was significantly reduced from 474.0 +/- 135.1 mu m at baseline to 333.4 +/- 135.6 at month-24 (p < 0.0001). Similarly, macular-volume (MV) was significantly reduced from 10.7 +/- 2.7 mm(3) at baseline to 9.6 +/- 2.9 mm(3) (p = 0.0027) at month-24. Among the 31 study eyes, 19 (61.3%) required an additional treatment for DME. Throughout the study, 9 (29.0%) eyes required ocular hypotensive medication for controlling their intraocular-pressure and 5 (16.1%) eyes underwent cataract surgery. Conclusions: In DME eyes who did not sufficiently respond to previous therapies, the FAc-i was associated with an improvement in visual and anatomic outcomes. There were no unexpected adverse-events.