To quantitatively evaluate changes in the sub-retinal pigment epithelial (RPE) space and determine the association with recurrent neovascular age-related macular degeneration (AMD). Twenty-two eyes treated with intravitreal aflibercept for treatment-naïve neovascular AMD were studied retrospectively. The sub-RPE area, volume, and central retinal thickness (CRT) were evaluated 1 and 2 months after the loading phase using spectral-domain optical coherence tomography. Recurrence was defined as newly detected neovascular activity during the 6 months after the loading phase. In eyes with recurrent AMD, the sub-RPE area increased significantly (P = 0.036) from 1 to 2 months after the loading phase and the sub-RPE volume increased marginally (P = 0.06). Subgroup analysis showed significant (P = 0.008 and P = 0.016, respectively) increases in the sub-RPE area and volume in typical AMD. In eyes with no recurrence, no significant changes occurred in the two parameters. No significant CRT changes occurred in eyes with or without a recurrence. A quantitative analysis demonstrated an increased likelihood of the sub-RPE space shortly after the loading phase in eyes with recurrent AMD; no changes occurred in eyes without a recurrence. These early changes in the sub-RPE space could indicate disease activity and are valuable for predicting recurrences of neovascular AMD.