Prevalence of persistent central-involved diabetic macular edema (DME) through 24 weeks of anti-vascular endothelial growth factor therapy and its longer-term outcomes may be relevant to treatment.To assess outcomes of DME persisting at least 24 weeks after randomization to treatment with 2.0-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab.Post hoc analyses of a clinical trial, the DRCR.net Protocol T among 546 of 660 participants (82.7%) meeting inclusion criteria for this investigation.Six monthly intravitreous anti-vascular endothelial growth factor injections (unless success after 3 to 5 injections); subsequent injections or focal/grid laser as needed per protocol to achieve stability.Persistent DME through 24 weeks, probability of chronic persistent DME through 2 years, and at least 10-letter (≥ 2-line) gain or loss of visual acuity.The mean age of participants was 60 years, 363 (66.5%) were white, and 251 (46.0%) were women. Persistent DME through 24 weeks was more frequent with bevacizumab (118 of 180 [65.6%]) than aflibercept (60 of 190 [31.6%]) or ranibizumab (73 of 176 [41.5%]) (aflibercept vs bevacizumab, P < .001; ranibizumab vs bevacizumab, P < .001; and aflibercept vs ranibizumab, P = .05). Among eyes with persistent DME through 24 weeks (n = 251), rates of chronic persistent DME through 2 years were 44.2% with aflibercept, 68.2% with bevacizumab (aflibercept vs bevacizumab, P = .03), and 54.5% with ranibizumab (aflibercept vs ranibizumab, P = .41; bevacizumab vs ranibizumab, P = .16). Among eyes with persistent DME through 24 weeks, proportions with vs without chronic persistent DME through 2 years gaining at least 10 letters from baseline were 62% of 29 eyes vs 63% of 30 eyes (P = .88) with aflibercept, 51% of 70 vs 55% of 31 (P = .96) with bevacizumab, and 45% of 38 vs 66% of 29 (P = .10) with ranibizumab. Only 3 eyes with chronic persistent DME lost at least 10 letters.Persistent DME was more likely with bevacizumab than with aflibercept or ranibizumab. Among eyes with persistent DME,...