© 2021, Sociedade Brasileira de Endocrinologia e Metabologia. All rights reserved.Objective: Thyroid nodules located in isthmus were found less prevalent, although papillary thyroid cancer in this location was reported to be more aggressive behaviour in some studies. Our aim was to evaluate hormonal,ultrasonographic, and cytopathologic features of nodules located in isthmus (isthmic nodules). Subjects and methods: Patients who underwent thyroidectomy between 2006-2014 reviewed retrospectively. Hormonal, ultrasonographic, and cytopathologic features compared between patients with isthmic (Group-1) and with lober (non-isthmic, Group-2) nodules. Results: Group-1 and Group-2 consisted of 251 and 2076 patients, respectively. 260 isthmic (5.5%) and 4433 non-isthmic (94.5%) nodules were compared.However,most ultrasonographical features such as presence of microcalcification and halo, diameters, echogenicity, texture, margin, and vascularity were similar between groups, macrocalcification rate was lower in isthmic nodules (18.8%, 25.9%; p = 0.012). Cytologic results were also similar.Although malignancy rate was lower in isthmic nodules (6.2%, 12.5%; p = 0.002), type of thyroid cancer was similar in isthmic and non-isthmic nodules.When malignant isthmic (n = 16,2.8%) and malignant non-isthmic nodules (n = 553, 97.2%) were compared, diameter and type of tumor, lymphovascular and capsular invasions, extrathyroidal extension and multifocality rates were not statistically significant.Malignant isthmic nodules (n = 16, 6.2%) had smaller size [10.1 (7.5-34.5) mm, 19.95 (8.4-74.1) mm; p = 0.002], and higher hypoechogenicity rate (31.3%, 5.7%, p = 0.003) compared to benign isthmic nodules (n = 244, 93.8%). Negative predictive value was higher and positive predictive value was lower in isthmic nodules compared to non-isthmic nodules (p = 0.033, p = 0.047, respectively). Conclusion: Isthmic nodules appear to be indolent because of having lower malignancy rate. FNAB might be required in isthmic nodules even if it has relatively small size. The surgery with limited extent or follow-up might seem to be reliable in the management of patients having isthmic nodules especially with indeterminate cytology. Arch Endocrinol Metab. 2021;65(3):277-88.