Polypoidal choroidal vasculopathy (PCV) is a hemorrhagic fundus disease that can lead to permanent vision loss. Predicting the treatment response to anti-VEGF monotherapy in PCV is consistently challenging. We aimed to conduct a prospective multicenter study to explore and identify the imaging biomarkers for predicting the anti-VEGF treatment response in PCV patients, establish predictive model, and undergo multicenter validation.This prospective multicenter study utilized clinical characteristics and images of treatment naïve PCV patients from 15 ophthalmic centers nationwide to screen biomarkers, develop model, and validate its performance. Patients from Peking Union Medical College Hospital were randomly divided into a training set and an internal validation set. A nomogram was established by univariate, LASSO regression, and multivariate regression analysis. Patients from the other 14 centers served as an external test set. Area under the curve (AUC), sensitivity, specificity, and accuracy were calculated. Decision curve analysis (DCA) and clinical impact curve (CIC) were utilized to evaluate the practical utility in clinical decision-making.The eye distribution for the training set, internal validation set, and external test set were 66, 31, and 71, respectively. The 'Good responder' exhibited a thinner subfoveal choroidal thickness (SFCT) (230.67 ± 61.96 vs. 314.42 ± 88.00 μm, p < 0.001), lower choroidal vascularity index (CVI) (0.31 ± 0.08 vs. 0.36 ± 0.05, p = 0.006), fewer choroidal vascular hyperpermeability (CVH) (31.0 vs. 62.2%, p = 0.012), and more intraretinal fluid (IRF) (58.6 vs. 29.7%, p = 0.018). SFCT (OR 0.990; 95% CI 0.981-0.999; p = 0.033) and CVI (OR 0.844; 95% CI 0.732-0.971; p = 0.018) were ultimately included as the optimal predictive biomarkers and presented in the form of a nomogram. The model demonstrated AUC of 0.837 (95% CI 0.738-0.936), 0.891 (95% CI 0.765-1.000), and 0.901 (95% CI 0.824-0.978) for predicting 'Good responder' in the training set, internal validation set, and external test set, respectively, with excellent sensitivity, specificity, and practical utility.Thinner SFCT and lower CVI can serve as imaging biomarkers for predicting good treatment response to anti-VEGF monotherapy in PCV patients. The nomogram based on these biomarkers exhibited satisfactory performances.