Abstract Disclosure: N. Angelopoulos: None. I. Iakovou: None. D. Goulis: None. R. Paparodis: None. S. Livadas: None. A. Boniakos: None. J.C. Jaume: None. Background: The frequency of papillary thyroid carcinoma (PTC) has increased, mainly due to the detection of small tumors incidentally found during unrelated imaging. While most of these small cancers have a non-aggressive course, some can be more biologically hostile, with potential for metastasis. Current guidelines discourage routine biopsy for nodules ≤10 mm, but the challenge is identifying higher-risk microcarcinomas. This study aims to identify ultrasound and clinical characteristics indicating malignancy in small thyroid lesions. Patients and methods: 151 patients with accidentally discovered solid nodules in thyroid ultrasound were enrolled in the study. All patients were stratified according to both ACR and EU-TIRADS systems. Two qualified endocrinologists performed ACR-TIRADS scoring and accordingly, all patients were stratified to the five ACR categories TR1-5 Strain elastography was also performed in all nodules and the elastography ratio (E2/E1) was calculated (E2 elastography of the nodule, E1 elastography of healthy thyroid gland). FNA was performed in nodules classified as EU-TIRADS 5 Results: 41 patients were classified as EU-TIRADS 5. The rest of the patients were classified as 69 EU-TIRADS 4, 40 EU-TIRADS 3, and one EU-TIRADS 2. According to FNA results, 11 patients had Bethesda II cytology (Group A), 2 Bethesda III, one Bethesda IV, 10 Bethesda V, and 17 Bethesda VI (V and VI comprised Group B). FNAs indicative of malignancy (Group B) were more frequent in patients with autoimmune thyroiditis (Chi-squared 5,833, df(1), p=0.015). In Group B, both ACR-scoring points and ACR-TIRADS categories were significantly higher than those detected in patients in Group A. Logistic regression analysis revealed a significant prognostic role of ACR-scoring points in discriminating suspicious FNA results for thyroid cancer. ROC analysis (AUC:0.993 with Youden Index:0.926, associated criterion >6, Sensitivity 92.59 % and Specificity 100 %). To analyze the predictive power of the clinical parameters in the presence of thyroid malignancy, age, BMI, gender, autoimmune disease, therapy, nodule diameter, and elastography ratio were examined in a “clinical model”. The overall prognostic value of the model was significant (p=0.0029, AUC:0.744) with a sensitivity of 77.78% and specificity of 72.73%, (Youden Index: 0.505, associated criterion >0.6). Finally, a “mixed model”, combining the clinical characteristics and the ACR scoring points, was generated for methodological reasons. The model was overall significant (p<0.001) with AUC:1 (95% Confidence interval: 0.907 to 1), Youden Index:1, sensitivity, and specificity 100%. Conclusion: ACR- TIRADS points > 6 may be a strong indicator of thyroid malignancy and the “mixed model” is an excellent predictor of thyroid malignancy, but its usefulness in everyday clinical practice may be cumbersome. Presentation: 6/1/2024