This study aimed to assess the efficacy and safety of anti-VEGF combined with dexamethasone implant for the retinal vein occlusion patients with macular edema. In this prospective, case-controlled, cohort clinical trial (Register ID: ChiCTR2400080048), patients with non-ischemic retinal vein occlusion were enrolled from the Sanmenxia Central Hospital from August 2020 to April 2023. The patients were randomized into two groups. All the patients received ranibizumab intravitreal injection in the first 3 consecutive months. For the ranibizumab group, anti-VEGF injections were as needed thereafter in case of recurrence of macular edema; For the combination group, the patients received an intravitreal dexamethasone implant injection at 15 days after the first ranibizumab injection. The primary outcome measurements were improvement in best corrected visual acuity (BCVA) and reduction in central macular thickness (CMT). The secondary outcomes were recurrence of macular edema, number of intravitreal injections, and injection interval. Safety profiles were also recorded. A total of 124 patients were included, of which 73 patients completed all follow-ups. Both the ranibizumab monotherapy and the combination therapy significantly improved BCVA at all time points, compared to the baseline. The combined group achieved more BCVA improvement in 3 months, 6 months, and 12 months, compared to the ranibizumab alone group. Compared to the baseline, both groups achieved significant reductions in CMT at all follow-ups. However, the combination group showed more CMT reduction at 1 week post injection, compared to the ranibizumab group. The combination group had a significantly longer injection interval, lower injection time, and recurrence of macular edema. Ocular hypertension was the most common adverse events. Lastly, intraocular pressure was all well controlled by 1-3 glaucoma medications without surgical intervention. The combination therapy could significantly improve the BCVA and reduce the CMT with a good safety profile.