Objective To compare the value of the thyroid imaging reporting and data system proposed by Kwak (KWAK TI-RADS) and the 2015 American Thyroid Association (ATA) guidelines for diagnosis of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC). To confirm the role of cell block (CB)-assisted fine-needle aspiration (FNA) in final diagnosis of MTC. Design Retrospective hospital-based cohort study. Patients Ninety-three patients with 29 MTCs, 31 PTCs and 33 thyroid adenomas (TAs) who underwent thyroidectomy from January 2010 to May 2019 were retrospectively reviewed. The KWAK TI-RADS and ATA guidelines were used to assess each thyroid nodule. FNA, CB-assisted FNA and core needle biopsy (CNB) were performed in final diagnosis. Results Age and ultrasound features (composition, echogenicity and shape) were significantly different between MTC and PTC. Sex and ultrasound features (echogenicity, margin and calcification) were significantly different between MTC and TA. The KWAK TI-RADS and ATA guidelines showed no significant difference for MTC (area under the curve [AUC]: 0.812 and 0.808; P = .37-.85) or PTC (AUC: 0.883 and 0.885; P = .25-.96). The KWAK TI-RADS and ATA guidelines showed high specificity and sensitivity for MTC (93.9% and 62.1%, 87.9% and 65.5%) and PTC (93.9% and 67.7%, 87.9% and 77.4%), respectively. For suspicious MTC (7 cases), CB-assisted FNA provide accuracy preoperative diagnosis. Conclusions Although the diagnostic performance of the TI-RADS and ATA guidelines is worse for MTC than PTC, the difference is not statistically significant. CB-assisted FNA should be performed in thyroid nodules with 4a or lower suspicion to avoid misdiagnosis of MTC.