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 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 eyes with CRVO received more injections (8.4 ± 2.4) than CRVO nonprogressors (6.2 ± 2.8; P = .01). Only 18.5% of fellow eyes progressed. Paired analysis showed greater change in vitreomacular staging in eyes with CRVO vs fellow eyes (mean, 0.44; P = .047). Conclusions: Eyes with CRVO receiving multiple IVT injections showed significantly greater progression toward complete PVD than untreated fellow eyes.