Purpose <p>To investigate the predictors of anatomical response in patients with diabetic macular edema (DME) following anti-vascular endothelial growth factor (anti-VEGF) therapy and establish a nomogram model for predicting the probability of anatomical response.</p> Methods <p>This study enrolled 200 DME patients treated with anti-VEGF regimen. Based on the reduction rate of central macular thickness (CMT) following treatment, patients were classified into an anatomical weak responder group (CMT reduction &lt; 20%) and an anatomical responder group (CMT reduction ≥ 20%). Baseline clinical data and OCT biomarkers were analyzed with multivariate logistic regression. A nomogram model was constructed by using R software. Bootstrapping was used for model validation, receiver operating characteristic (ROC) curve and calibration curve were used for evaluating the discrimination and calibration of prediction model, and decision analysis curve (DCA) was used for evaluating the practicality of model.</p> Results <p>Predictors for anatomical response in DME patients are serum creatinine (Scr), CMT, photoreceptor outer segment length (PROSL), and cystoid macular edema (CME) presence as independent variables. The nomogram prediction model based on the above four predictors had good representativeness (Bootstrap method: precision: 0.820), differentiation [the area under curve (AUC) value: 0.819], and the DCA analysis showed that the prediction model, whose threshold probability was in the range of 0 to 1, had clinical practical value.</p> Conclusion <p>The anatomical response to anti-VEGF treatment for DME is independently associated with baseline Scr, CMT, PROSL, and the presence of CME.</p>