The first-line treatment for prolactinoma is drug therapy with dopamine agonists (DAs). However, some patients with resistance to DA treatment should prioritize surgical treatment. Therefore, it is crucial to accurately identify the drug treatment response of prolactinoma before treatment. The present study was performed to determine the DA treatment response of prolactinoma using a clinical radiomic model that incorporated radiomic and clinical features before treatment.In total, 255 patients diagnosed with prolactinoma were retrospectively divided to training and validation sets. An elastic net algorithm was used to screen the radiomic features, and a fusion radiomic model was established. A clinical radiomic model was then constructed to integrate the fusion radiomic model and the most important clinical features through multivariate logistic regression analysis for individual prediction. The calibration, discrimination, and clinical applicability of the established models were evaluated. 60 patients with prolactinoma from other centers were used to validate the performance of the constructed model.The fusion radiomic model was constructed from three significant radiomic features, and the area under the curve in the training set and validation set was 0.930 and 0.910, respectively. The clinical radiomic model was constructed using the radiomic model and three clinical features. The model exhibited good recognition and calibration abilities as evidenced by its area under the curve of 0.96, 0.92, and 0.92 in the training, validation, and external multicenter validation set, respectively. Analysis of the decision curve showed that the fusion radiomic model and clinical radiomic model had good clinical application value for DA treatment response prediction in patients with prolactinoma.Our clinical radiomic model demonstrated high sensitivity and excellent performance in predicting DA treatment response in prolactinoma. This model holds promise for the noninvasive development of individualized diagnosis and treatment strategies for patients with prolactinoma.Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.