Background: The leading cause of blindness due to non-infectious uveitis is cystoid macular edema (CME). Behçet’s disease (BD) is one of the most commonly conditions related to CME. Objectives: To compare the effectiveness and safety of adalimumab (ADA), infliximab (IFX) and certolizumab (CZP) in refractory CME due to BD. Methods: Multicenter study of BD-CME patients with no response to glucocorticoids (GCs) and at least one conventional immunosuppressive drug. At baseline, all patients presented CME, defined by OCT > 300 µ. The effectiveness of ADA, IFX and CZP was assessed over a 2-year period from baseline using the following ocular parameters: macular thickness (µm), visual acuity (BCVA), anterior chamber (AC) cells and vitritis. Mixed-effects regression models were applied. Results: a total of 50 patients (75 eyes) were studied (ADA = 25; IFX = 15 and CZP = 10). No significant differences in demographic parameters were found among the three groups. However, individuals in the CZP group had a significantly extended time from diagnosis to treatment onset (72 (36–120) months, p = 0.03) and had received a higher number of biological therapies (1.7 ± 1.1) compared to the ADA and IFX groups. Within the CZP group, ADA and IFX were previously administrated in seven patients. After 2 years of follow-up, a rapid and sustained reduction in macular thickness was noted in all three groups with no significant differences between them. Additionally, enhancements in BCVA, AC cells and vitritis were also observed. No serious adverse events were reported in the CZP group, although one isolated case of bacteremia was documented in the ADA group. ADA, IFX and CZP appear to be effective and safe treatments for refractory CME in BD. CZP seems to remain effective even in patients with an insufficient response to ADA and/or IFX. Conclusions: ADA, IFX and CZP appear to be effective and safe treatments for refractory CME in BD. CZP seems to remain effective even in patients with an insufficient response to ADA and/or IFX.