Purpose: To assess the impact of repeated intravitreal (IVT) antivascular endothelial growth factor (anti-VEGF) injections on the vitreomacular interface in eyes with cystoid macular edema secondary to central retinal vein occlusion (CRVO). Methods: This retrospective cohort study included 45 treatment-naïve eyes with CRVO with 12 or more months of follow-up. The cohort had a mean (±SD) age of 62 ± 12 years, was 40% male, and was racially diverse (60% White, 29% Black). All eyes received more than 1 anti-VEGF injection. Vitreomacular status was staged at baseline and 12 months using optical coherence tomography. Eyes with complete posterior vitreous detachment (PVD) at presentation or previous treatment for CRVO were excluded. Twenty-seven untreated fellow eyes served as controls. Results: PVD progression occurred in 42% of eyes with CRVO, with 4% reaching complete PVD. The 19 eyes with CRVO that progressed received more injections (mean, 8.4 ± 2.4) than the 26 CRVO nonprogressors (mean, 6.2 ± 2.8; P = .01). Only 18.5% of fellow eyes progressed. Analysis of paired data from 27 eyes with CRVO and 27 fellow eyes showed greater change in vitreomacular stage from presentation to 12 months in eyes with CRVO vs fellow eyes (mean difference, 0.44; P = .047). Conclusions: Eyes with CRVO receiving multiple IVT injections showed significantly greater progression toward complete PVD than untreated fellow eyes.