Objective: This study aims to determine the effect of intraretinal (IRF) and subretinal (SRF) fluid on visual outcomes for diabetic macular edema (DME) patients treated with anti-vascular endothelial growth factor (anti-VEGF) in routine clinical practice.Design: Optical coherence tomography scans were analyzed with a deep-learning artificial intelligence software to quantify IRF, SRF, and total retinal fluid (TRF) at baseline and at 3, 6, and 12 months. Predictive variables for best-corrected visual acuity (BCVA) were evaluated with linear mixed-effects regression models.Participants: A total of 220 DME eyes of 220 patients from the Cole Eye Institute at Cleveland Clinic.Methods: Retrospective, nonrandomized cohort study.Results: BCVA improved from baseline to 12 months (63.36 +/- 14.72 to 68.49 +/- 13.14 Early Treatment Diabetic Retinopathy Study letters, p < 0.001, respectively). Central subfield thickness improved from baseline to 12 months (411.74 +/- 129.7 to 335.94 +/- 116.91 mm, p < 0.001, respectively). Injection frequency per patient was 8.25 +/- 2.5 injections over 12 months. The linear mixed-effects regression model in the foveal region for TRF, IRF, and SRF volume at the fourth quartile showed BCVA losses of -8.29 letters (range, -10.96 to -5.62 letters, p < 0.001), -7.52 letters (range, -10.3 to -4.74 letters, p < .001), and -6.93 letters (range, -10.54 to -3.41 letters, p < .001), respectively.Conclusions: The highest quartile of TRF, IRF, and SRF volumes led to worse visual outcomes after 12 months of anti-VEGF treatment in patients with DME. Further studies designed to investigate the effect of anti-VEGF treatment on retinal fluid morphology could provide greater insight into individualized DME treatment.