Purpose To assess the functional and anatomical outcomes of concurrent administration of aflibercept injection and dexamethasone (DEX) implant in patients with macular edema (ME) secondary to retinal vein occlusion (RVO), refractory to each of the two drugs previously administered as monotherapy. Secondary outcomes included the number of retreatments required in a 12-month follow-up and safety. Methods This is a prospective, interventional case series of consecutive patients with refractory ME secondary to RVO, followed over a year. One injection of aflibercept was followed by a DEX implant on the same day; retreatment was driven by the persistence of ME on SD-OCT at least 4 months after the previous combined therapy. Central retinal thickness (CRT), best-corrected visual acuity (BCVA), and intraocular pressure (IOP) were collected at 1 month and then every 2 months until the end of follow-up. Results Thirty eyes of 30 Caucasian patients were enrolled; mean duration of RVO before the first combined treatment was 25 ± 5 months (range 11 ± 30). Baseline BCVA was 0.73 ± 0.5 LogMAR, with no significant changes at 12 months (0.77 ± 0.51 μm, p  = 0.2). Baseline CRT was 578.3 ± 161 μm, reducing to 352.5 ± 81 μm at 12 months ( p  = 0.003). Thirteen eyes (43.3%) required a second treatment. Twenty eyes (66.6%) showed no ME at the end of follow-up. One patient (3.3%) required topical IOP-lowering therapy during the study. Conclusion In eyes with ME secondary to RVO unresponsive to either aflibercept or DEX administered singularly, a combination therapy with simultaneous administration of aflibercept and DEX was effective in resolving ME, despite the absence of visual improvement. Earlier combined treatment in the course of the disease might lead to better functional outcomes.