Objective:Bethesda System for Reporting Thyroid Cytopathology (BSRTC) categories Ⅰ,Ⅲ,and Ⅴ account for a significant proportion of fine needle aspiration cytology (FNAC) diagnoses.This study aimed to compare the diagnostic efficacy of BRAEV600E mutation and the Thyroid Imaging Reporting and Data System (TIRADS) classification in differentiating papillary thyroid cancers (PTCs) from benign lesions among BSRTC Ⅰ,Ⅲ,and Ⅴ nodules.Methods:A total of 472 patients with 479 nodules were enrolled in this prospective study.Ultrasound,BRAEV600E mutation testing,and FNAC were performed in each nodule,followed by surgery or regular ultrasound examination.Results:In the BSRTC I category,BRAEV600E showed similar sensitivity,higher specificity,and lower accuracy when compared with TIRADS.In the BSRTC Ⅲ/Ⅴ category,the sensitivity,specificity,and accuracy of BRAFV600E were similar to those of TIRADS.In comparison to BRAFV600E alone,the combination of the two methods significantly improved sensitivity (BSRTC Ⅰ:93.6％ vs.67.7％,P ＜ 0.01;BSRTC Ⅲ:93.8％ vs.75.0％,P ＜ 0.01;BSRTC Ⅴ:96.0％ vs.85.3％,P ＜ 0.001).When compared with TIRADS alone,the combination improved sensitivity in BSRTC I nodules (93.6％ vs.74.2％,P ＜ 0.05),increased sensitivity and decreased accuracy in BSRTC Ⅲ nodules (93.8％ vs.75.0％,P ＜ 0.01,91.0％ vs.93.6％,P ＜ 0.01),and improved both sensitivity and accuracy in BSRTC Ⅴ nodules (96.0％ vs.82.0％,P ＜ 0.001;94.2％ vs.81.3％,P ＜ 0.001).Conclusions:BRAEV600E exhibited higher specificity and lower accuracy compared with TIRADS in BSRTC Ⅰ nodules,while the two methods showed similar diagnostic value in BSRTC Ⅲ/Ⅴ nodules.The combination of the two methods distinctly improved sensitivity in the diagnosis of PTCs in BSRTC Ⅰ,Ⅲ,and Ⅴ nodules.