PURPOSE: Machine learning models based on radiomic feature extraction from clinical imaging data provide effective and interpretable means for clinical decision making. This pilot study evaluated whether radiomics features in baseline optical coherence tomography (OCT) images of eyes with pigment epithelial detachment (PED) associated with neovascular age-related macular degeneration (nAMD) can predict treatment response to as-needed anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Thirty-nine eyes of patients with PED undergoing anti-VEGF therapy were included. All eyes underwent a loading dose followed by as-needed therapy. OCT images at baseline, month 3, and month 6 were analyzed. Images were manually separated into non-responding, recurring, and responding eyes based on the presence or absence of subretinal fluid at month 6. PED radiomics features were then extracted from each image and images were classified as responding or recurring using a machine learning classifier applied to the radiomics features. RESULTS: Linear discriminant analysis classification of baseline features as responsive versus recurring resulted in classification performance of 64.0% (95% confidence interval [CI] = 0.63-0.65), area under the curve (AUC = 0.78, 95% CI = 0.72-0.82), sensitivity 0.79 (95% CI = 0.63-0.87), and specificity 0.58 (95% CI = 0.50-0.67). Further analysis of features in recurring eyes identified a significant shift toward non-responding mean feature values over 6 months. CONCLUSIONS: Our results demonstrate the use of radiomics features as predictors for treatment response to as-needed anti-VEGF therapy. Our study demonstrates the potential for radiomics feature in clinical decision support for personalizing anti-VEGF therapy. TRANSLATIONAL RELEVANCE: The ability to use PED texture features to predict treatment response facilitates personalized clinical decision making.