PURPOSE To review the results of Diabetic Retinopathy Clinical Research Network Protocol T, as applied to clinical practice. METHODS Review of major publications reporting the results of Protocol T, a randomized single-masked (in year-1 only), multicenter clinical trial comparing aflibercept, bevacizumab, and ranibizumab as treatment option for center-involving diabetic macular edema (DME). The main outcome measures were change in visual acuity (VA), central subfield thickness (CST) on optical coherence tomography, cost effectiveness, burden of care, and safety. RESULTS A total of 660 participants (mean age 61 ± 10 years, 47% women, 65% Caucasian) were randomized to treatment with aflibercept (n = 224), ranibizumab (n = 218), or bevacizumab (n = 218). The majority of patients (90%) had type II diabetes, with an average duration of 17 ± 11 years. About half the patients had baseline ETDRS VA of 20/32 to 20/40, and half had ETDRS VA of 20/50 to 20/320 in all 3 cohorts. Patients in all 3 cohorts received a similar number of injections during the study period (9-10 in year-1; 5-6 in year-2). The year-1 improvement in ETDRS letters was significantly higher for aflibercept than for ranibizumab and bevacizumab in patients with baseline VA 20/50 or worse (p = 0.003 and p < 0.001, respectively), but was no different in patients with better baseline VA of 20/32 to 20/40 (p = 0.69). By year-2, among patients with poorer baseline VA, there was a difference in mean letters gained between aflibercept and bevacizumab (p = 0.02), but no difference between aflibercept and ranibizumab (p = 0.18). At year-2, there was no clinically meaningful difference in VA improvement (i.e., gain or loss of ≥10 or ≥15 letters) among any of the agents (p > 0.74). Bevacizumab was less effective than the other agents in decreasing CST at years-1 and -2 in the overall cohort of patients (p < 0.001). However, bevacizumab is substantially cheaper and much more cost-effective (when comparing expense and quality of life measures) than aflibercept and ranibizumab. The cost of other agents would have to decrease by 80-90% to be cost-effective relative to bevacizumab. Intravitreal administration of anti-VEGF therapy has relatively few ocular and systemic side effects, but caution may be warranted for patients with a recent history or high risk of myocardial infarction or stroke. CONCLUSIONS Aflibercept, bevacizumab, and ranibizumab are highly effective treatments for DME. Bevacizumab is more cost-effective than aflibercept and ranibizumab. Intravitreal administration of drugs is relatively safe; however, intravitreal administration may be associated with severe systemic side effects in a small percentage of patients, particularly in those with a prior history of or high risk of Anti-Platelet Trialists' Collaboration events.