OBJECTIVE: To compare the diagnostic performance and the unnecessary biopsy rates for recommending fine needle aspiration (FNA) of Thyroid Imaging Reporting and Data Systems proposed by American College of Radiology (ACR TI-RADS), American Thyroid Association (ATA) guidelines, TI-RADS proposed by Kwak (Kwak TI-RADS), and Korean Thyroid Association/Korean Society of Thyroid Radiology (KTA/KSThR) guidelines for malignancy risk stratification of thyroid nodules (TNs). METHODS: The study included 1271 TNs whose cytologic results or surgical pathologic findings were available. Ultrasound images of these TNs were retrospectively reviewed and categorized according to the four guidelines. The diagnostic performances and the unnecessary biopsy rates for recommending FNA of the four guidelines were evaluated. RESULTS: After multivariate analysis, the most significant independent predictor for malignancy was hypoechogenicity/marked hypoechogenicity (OR: 9.37, 95% CI: 5.40-16.26) (P < 0.001) among the suspicious ultrasound images features. For all nodules and two subgroups (i.e. nodules <10 mm group and nodules ≥10 mm group), ACR TI-RADS demonstrated higher specificities (all P < 0.05) and lower sensitivities (all P < 0.001) than the other guidelines. In the all nodules group and the nodules<10 mm group, ACR TI-RADS and Kwak TI-RADS had higher Azs than the other guidelines (all P < 0.01). The unnecessary biopsy rates for recommending FNA of ACR TI-RADS in the all nodules (≥10 mm) group and the subgroup (10∼19 mm) were all lower than those of the others guidelines (P < 0.001 for all). For the subgroup (≥20 mm), the unnecessary biopsy rate of ACR was lower than that of ATA guidelines and KTA/KSThR guidelines (P < 0.001). CONCLUSIONS: The four guidelines have good diagnostic efficiency in differentiating TNs. ACR TI-RADS and Kwak TI-RADS have better diagnostic performance than the other guidelines in the all nodules group and the nodules<10 mm group. Considering the comprehensive diagnostic efficacy and unnecessary biopsy rate, ACR TI-RADS is a more desirable classification guideline in clinical practice.