Purpose <p>Although papillary thyroid carcinoma (PTC) is generally associated with a favorable prognosis, progression to radioactive iodine-refractory (RAIR) disease in metastatic cases leads to significantly poorer clinical outcomes. This study aimed to analyze the clinical value of clinicopathological, pre-operative ultrasonographic features, and fibroblast activation protein (FAP) immunoreactivity scores for the pretherapeutic prediction of the efficacy of radioiodine (RAI, ¹³¹I) treatment in PTC.</p> Methods <p>A retrospective analysis was conducted on the medical records, clinicopathological data, and pre-operative ultrasonographic imaging of 167 PTC patients treated with ¹³¹I (113 clinical complete remission group, 54 RAIR group). Their specimens were collected for FAP immunohistochemical staining and scoring. Statistical analyses were performed to identify RAIR risk factors and a predictive model for RAIR PTC was established.</p> Results <p>Binary logistic regression analysis revealed that a maximum tumor diameter of ≥ 17.5&#xa0;mm, microcalcifications, and a FAP immunoreactivity score of ≥ 3.44 were identified as independent risk factors for RAIR PTC. The combined model showed high sensitivity (75.9%), specificity (77.0%), and accuracy (AUC = 0.812) in the pretherapeutic prediction of ¹³¹I therapeutic efficacy in PTC. Furthermore, calibration curve and decision curve analysis (DCA) confirmed that the combined predictive model exhibited good accuracy and clinical utility.</p> Conclusion <p>Clinical significance was observed in the clinicopathological characteristics, ultrasonographic features of PTC and FAP immunoreactivity scores for evaluating ¹³¹I therapeutic efficacy. High sensitivity, specificity, and diagnostic accuracy were achieved when a maximum tumor diameter of ≥ 17.5&#xa0;mm, microcalcifications, and a FAP immunoreactivity score of ≥ 3.44 were combined for assessment.</p>