To provide 2-year results comparing anti-vascular endothelial growth factor (VEGF) agents for center-involved diabetic macular edema (DME) using a standardized follow-up and retreatment regimen. Randomized clinical trial. Six hundred sixty participants with visual acuity (VA) impairment from DME. Randomization to 2.0-mg aflibercept, 1.25-mg repackaged (compounded) bevacizumab, or 0.3-mg ranibizumab intravitreous injections performed up to monthly using a protocol-specific follow-up and retreatment regimen. Focal/grid laser photocoagulation was added after 6 months if DME persisted. Visits occurred every 4 weeks during year 1 and were extended up to every 4 months thereafter when VA and macular thickness were stable. Change in VA, adverse events, and retreatment frequency. Median numbers of injections were 5, 6, and 6 in year 2 and 15, 16, and 15 over 2 years in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P = 0.08). Focal/grid laser photocoagulation was administered in 41%, 64%, and 52%, respectively (aflibercept vs. bevacizumab, P < 0.001; aflibercept vs. ranibizumab, P = 0.04; bevacizumab vs. ranibizumab, P = 0.01). At 2 years, mean VA improved by 12.8, 10.0, and 12.3 letters, respectively. Treatment group differences varied by baseline VA (P = 0.02 for interaction). With worse baseline VA (20/50 to 20/320), mean improvement was 18.1, 13.3, and 16.1 letters, respectively (aflibercept vs. bevacizumab, P = 0.02; aflibercept vs. ranibizumab, P = 0.18; ranibizumab vs. bevacizumab, P = 0.18). With better baseline VA (20/32 to 20/40), mean improvement was 7.8, 6.8, and 8.6 letters, respectively (P > 0.10, for pairwise comparisons). Anti-Platelet Trialists' Collaboration (APTC) events occurred in 5% with aflibercept, 8% with bevacizumab, and 12% with ranibizumab (global P = 0.047; aflibercept vs. bevacizumab, P = 0.34; aflibercept vs. ranibizumab, P = 0.047; ranibizumab vs. bevacizumab, P = 0.20; global P = 0.09 adjusted for potential confounders). All 3 anti-VEGF groups showed VA improvement from baseline to 2 years with a decreased number of injections in year 2. Visual acuity outcomes were similar for eyes with better baseline VA. Among eyes with worse baseline VA, aflibercept had superior 2-year VA outcomes compared with bevacizumab, but superiority of aflibercept over ranibizumab, noted at 1 year, was no longer identified. Higher APTC event rates with ranibizumab over 2 years warrants continued evaluation in future trials.