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Introduction The fluocinolone acetonide (FAc) intravitreal drug-delivery system implant is a recent, second-line, intravitreal drug for the management of diabetic macular edema (DME). FAc acts against DME with a major anti-inflammatory effect. Despite the already proved efficacy, a number of patients still show persistent DME and require anti-VEGF retreatment. The main aim of the present study was to assess the relationship between quantitative biomarkers of inflammation and both DME recovery and the need for additional anti-VEGF in eyes treated by FAc implant. Methods The study was designed as prospective and interventional with 1 year of follow-up. We analyzed structural optical coherence tomography (OCT) quantitative biomarkers of inflammation, namely choroidal hyperreflective foci (HF) and the choroidal vascularity index (CVI), and we assessed the relationship with other clinically relevant biomarkers and the outcome achieved after 1 year. Moreover, we stratified DME eyes in good and poor responders to FAc implant to highlight clinically relevant differences. Results Our study included 50 eyes (50 patients) treated by FAc implant. We found significant best-corrected visual acuity (BCVA) and central macular thickness (CMT) improvements after 1 year. Good responders started with worse visual acuity and higher CMT than poor responders, but gained letters significantly at the end of the follow-up, whereas poor responders showed stable BCVA values. Good responders were characterized by significantly higher choroidal HF and lower CVI than poor responders. Poor responders required significantly higher additional anti-VEGF treatments. Conclusions Quantitative structural OCT biomarkers of inflammation allowed distinguishing different inflammatory profiles of DME. The inflammatory component helped to categorize DME eyes in good and poor responders to FAc implant.