Purpose To evaluate the association of fluid volatility with ellipsoid zone (EZ) integrity and subretinal hyperreflective material (SHRM) volume during anti–vascular endothelial growth factor (VEGF) therapy in neovascular age-related macular degeneration (nAMD). Methods This study was a post hoc analysis of the OSPREY study. Retinal volatility was quantified as the standard deviation across weeks 12 to 56 for six optical coherence tomography (OCT) metrics: central subfield thickness (CST), total fluid (TF) volume, subretinal fluid (SRF) volume, intraretinal fluid (IRF) volume, macular total retinal fluid index (TRFI), and central macular TRFI. Eyes with volatility ≤ 25th or ≥ 75th percentile values were compared. Results Eyes with low volatility in several exudative metrics showed greater change from baseline in SHRM volume at week 12 than eyes with high volatility. During the maintenance phase (weeks 12–56), eyes exhibiting high SRF volatility demonstrated increased SHRM volume compared to eyes with low SRF volatility ( P = 0.027). Eyes exhibiting high volatility in CST, TF, and SRF demonstrated less improvement in EZ total attenuation ( P < 0.001, P = 0.033, and P = 0.043, respectively) than eyes with low volatility. Early exudative instability (i.e., between weeks 4–8 or weeks 8–12) in multiple parameters (i.e., CST, TF, IRF, macular TRFI, or central macular TRFI) was associated with greater volatility during the maintenance phase ( P < 0.05). Conclusions Greater volatility in exudative OCT metrics, particularly SRF volatility, was associated with a greater increase in SHRM and less improvement in EZ integrity, suggesting that volatility is detrimental to multiple anatomic features in nAMD. Early exudative instability during the loading phase of treatment was associated with longer-term volatility in exudation.