AIM: To investigate the prevalence and clinical implications of hyperreflective walls (HRW) in foveal cystoid spaces in patients with cystoid macular edema (CME) caused by retinal diseases and noninfectious uveitis (NIU). METHODS: This retrospective cross-sectional study included 443 eyes with CME secondary to diabetic macular edema (DME), retinal vein occlusion (RVO), retinitis pigmentosa (RP), neovascular age-related macular degeneration (nAMD), and NIU. Demographic data, HRW features, and other spectral domain optical coherence tomography (SD-OCT) biomarkers were analyzed. RESULTS: HRW was observed in 40.9% of DME eyes (present, n=77, 38 males, 58.30±12.04y; absent, n=111, 50 males, 55.95±10.56y), 32.5% of RVO eyes (present, n=49, 22 males, 64.53±11.90y; absent, n=102, 42 males, 60.67±11.73y), 31.4% of nAMD eyes (present, n=16, 8 males, 70.13±7.75y; absent, n=35, 13 males, 73.91±9.11y), 57.1% of RP eyes (present, n=12, 4 males, 40.50±12.06y; absent, n=9, 4 males, 44.11±14.32y), and 18.8% of uveitic macular edema (UME) eyes (present, n=6, 3 males, 30.83±16.23y; absent, n=26, 12 males, 43.46±17.58y). HRW was significantly associated with vitreoretinal abnormalities [odds ratio (OR), 2.202; 95% confidence interval (95%CI), 1.342–3.613; P=0.002], hyperreflective foci (OR, 3.33; 95%CI, 1.884–5.883; P<0.001), inner retinal layer disorganization (OR, 1.816; 95%CI, 1.087–3.035; P=0.023), external limiting membrane disruptions (OR, 3.476; 95%CI, 1.839–6.574; P<0.001), and disrupted ellipsoid zone length (OR, 1.001; 95%CI, 1.000–1.002; P=0.04), and a high HRW height in the foveal cystoid spaces (OR, 1.003; 95%CI, 1.001–1.006; P=0.003). CONCLUSION: HRW in foveal cystoid spaces is a common OCT finding in CME and is associated with more severe retinal structural damage and worse visual acuity. HRW may be utilized as a prognostic OCT biomarker for disease severity and treatment response in patients with CME. This study suggests that early detection of HRW and optimization of treatment strategies may improve patient prognosis.