Purpose <p>Ultrasonography (US) is the most accurate and cost-effective imaging method for identifying thyroid nodules. The difficulty in determining which nodules to sample for fine-needle aspiration (FNA) cytology has prompted the introduction of the Thyroid Imaging Reporting and Data Systems (TIRADS), which assesses the malignancy risk associated with thyroid nodules. Real-time elastography (RTE), coupled with strain ratio (SR) measurements, offers a means to evaluate the nodule stiffness and potentially discern their likelihood of being malignant. The present study aimed to investigate the efficacy of RTE and SR, combined with the TIRADS grading systems, in distinguishing between benign and malignant thyroid nodules.</p> Methods <p>From 1094 patients with thyroid nodules referred for thyroid ultrasound at a University Hospital, those with thyroid nodules ≥20 mm in diameter were enrolled. Each nodule was categorized according to European (EU)- and American College of Radiology (ACR)-TIRADS systems, ranging from 2–5. Nodules’ SRs were evaluated together with RTE. The thyroid nodule diagnosis was documented by post-thyroidectomy histopathological examination and/or US-guided FNA according to the Bethesda classification of the examined smears.</p> Results <p>The study involved 267 patients (mean age 60.3 ± 14.3 years; 46 males and 221 females) with 308 nodules categorized into EU-TIRADS categories 3, 4, and 5. Of these nodules, 22 proved malignant, and 286 benign. The elastography ratio exhibited high predictive performance in diagnosing thyroid malignancy (p &lt; 0.001) at a threshold value of &gt;0.84 (sensitivity 90.9%, specificity 73.4%). In the 168 nodules with EU-TIRADS 3, this threshold had 100% sensitivity and 75.1% specificity in discriminating malignant thyroid nodules.</p> Conclusion <p>Combining TIRADS with data derived from RTE reduces unnecessary FNAs and surgeries in patients with thyroid nodular disease.</p>