Objective: To gain information about multiple dexamethasone intravitreal implant (DEX-I) injections in diabetic macular edema (DME) eyes in real-life clinical settings. Methods: Patients with DME treated with multiple (≥5) DEX-I injections between January 1, 2014, and December 31, 2018, were retrospectively enrolled regardless of previous treatment with anti-VEGF agents. All patients were evaluated with best-corrected visual acuity (BCVA) in logMAR, ocular fundus, and spectral domain optical coherence tomography (SD-OCT) at baseline and at 3 months after the last DEX-I injection. Multiple DEX-I injections were administered when necessary in case of DME recurrence. Main efficacy measures were changes in BCVA and central retinal thickness (CRT) from baseline to 3 months after the last DEX-I injection; main secondary measures were an increase in intraocular pressure (IOP), the need for cataract surgery, endophthalmitis, and vitreous hemorrhage. Results: Seventeen patients (18 eyes) with DME and mean age (± SD) of 54.3 ± 8.16 years were treated with DEX-I injections between 2014 and 2018. The majority of eyes (77.8%) had been treated with a mean of 6.3 ± 3.2 anti-VEGF agents before switching to DEX-I. During a mean follow-up period of 37.6 months and after a mean number of 5.9 DEX-I injections, visual acuity improved or stabilized in 77.8% of all eyes, accompanied by a significant reduction in CRT. An increase in IOP was recorded in 38.8% of all patients, while a surgical procedure was needed for cataract in 73.3% of all phakic patients. Conclusions: In this real-life experience in Italy, multiple DEX-I treatments showed good efficacy with no new safety concerns. The follow-up duration of >3 years and a greater number of DEX-I intravitreal injections compared to other observations confirm the positive balance between risks and benefits of DEX-I in the long term.