PURPOSE: The goal of this study was to evaluate the role of texture-based baseline radiomic features (Fr) and dynamic radiomics alterations (delta, FΔr) within multiple targeted compartments on optical coherence tomography (OCT) scans to predict response to anti-vascular endothelial growth factor (VEGF) therapy in neovascular age-related macular degeneration (nAMD). METHODS: HAWK is a phase 3 clinical trial data set of active nAMD patients (N = 1082) comparing brolucizumab and aflibercept. This analysis included patients receiving 6 mg brolucizumab or 2 mg aflibercept and categorized as complete responders (n = 280) and incomplete responders (n = 239) based on whether or not the eyes achieved/maintained fluid resolution on OCT. A total of 481 Fr were extracted from each of the fluid, subretinal hyperreflective material (SHRM), retinal tissue, and sub-retinal pigment epithelium (RPE) compartments. Most discriminating eight baseline features, selected by the minimum redundancy, maximum relevance feature selection, were evaluated using a quadratic discriminant analysis (QDA) classifier on the training set (Str, n = 363) to differentiate between the two patient groups. Classifier performance was subsequently validated on independent test set (St, n = 156). RESULTS: In total, 519 participants were included in this analysis from the HAWK phase 3 study. There were 280 complete responders and 219 incomplete responders. Compartmental analysis of radiomics featured identified the sub-RPE and SHRM compartments as the most distinguishing between the two response groups. The QDA classifier yielded areas under the curve of 0.78, 0.79, and 0.84, respectively, using Fr, FΔr, and combined Fr, FΔr, and Fc on St. CONCLUSIONS: Utilizing compartmental static and dynamic radiomics features, unique differences were identified between eyes that respond differently to anti-VEGF therapy in a large phase 3 trial that may provide important predictive value. TRANSLATIONAL RELEVANCE: Imaging biomarkers, such as radiomics features identified in this analysis, for predicting treatment response are needed to enhanced precision medicine in the management of nAMD.