Purpose: The purpose of this study was to report the short-term visual and anatomical outcomes after intravitreal injections of two different tumor necrosis factor α inhibitors in eyes with refractory diabetic macular edema. Methods: An interventional, retrospective, multicenter study of 39 eyes with refractory diabetic macular edema that were injected with adalimumab (n = 5 for 2 mg) or infliximab (n = 15 for 1 mg; n = 19 for 2 mg). The main outcome measures were the best-corrected visual acuity and the central macular thickness at 3 months of follow-up. Results: In the 1-mg infliximab group, the logarithm of the minimal angle of resolution best-corrected visual acuity improved from 1.49 ± 0.58 at baseline to 1.38 ± 0.56 at 3 months (P = 0.6991). In the 2-mg infliximab group, the logarithm of the minimal angle of resolution best-corrected visual acuity worsened from 0.76 ± 0.54 to 1.03 ± 0.69 at 3 months (P = 0.5995). In the adalimumab group, the logarithm of the minimal angle of resolution best-corrected visual acuity improved from 1.44 ± 0.77 to 1.08 ± 0.85 at 3 months (P = 0.2500). The central macular thickness in the 1-mg infliximab group decreased from 459 ± 125 μm at baseline to 388 ± 131 μm at 3 months (P = 0.1178). In the 2-mg infliximab group, the central macular thickness remained unchanged from 378 ± 97 μm at baseline to 349 ± 118 μm at 3 months (P = 0.2162). In the adalimumab group, the central macular thickness remained unchanged from 521 ± 163 μm at baseline to 526 ± 390 μm at 3 months (P = 0.1250). There were no systemic side effects reported in any of the patients. However, laboratory markers for autoimmunity were not done. None of the eyes injected with either adalimumab or 1 mg of infliximab had adverse ocular events. In the 2-mg infliximab group, 42% (8 of 19) of eyes developed severe uveitis. Three of these eyes (37.5%) required pars plana vitrectomy. The uveitis in the remaining five eyes resolved with topical steroid therapy. Conclusion: Both intravitreal adalimumab and infliximab do not appear to benefit eyes with refractory diabetic macular edema. Intravitreal injections of infliximab may elicit a severe intraocular inflammatory reaction. © The Ophthalmic Communications Society, Inc.