Background/objectives:Thyroid nodule (TN) is a common thyroid disorder globally, and the incidence has been increasing in recent decades. The objective of this study was to determine the contribution of thyroid-stimulating hormone (TSH), ultrasound (US), and cytological classification system for predicting malignancy among the surgically excised nodules.Design and methods:A retrospective analysis was performed between January 2012 and December 2014, using data drawn from 1188 patients (15-90 years), who had 1433 TN and fine-needle aspiration in Prince Sultan Military Medical City, Saudi Arabia. After reviewing all the thyroid cytopathological slides and US reports, classification was done based on the Bethesda System for Reporting Thyroid Cytology and the Thyroid Imaging Reporting and Data System (TI-RADS).Results:A total of 1188 patients’ medical records were reviewed for this study, among them 311 patients had undergone surgical intervention (253 patients had single nodule and 58 had 2 nodules), with a total of 369 nodules. However, as 54 nodules on the US were either unavailable or unclear, the 315 remaining nodules were analyzed, revealing 30.2% (n = 95) malignancy overall. Patients with TSH values of >4.5 mIU/L (38.2%), TN <1 cm (48.8%), TI-RADS category 5 (75.6%), and Bethesda category VI (88.9%) revealed a higher percentage of malignancy. From the univariate analysis using the χ2 test, significant relationship between the TSH, nodule size, TI-RADS, and the Bethesda category between the malignant and benign nodules emerged. The regression analysis showed that patients with a TSH value of 0.5 to 4.5 mIU/L (odds ratio [OR]: 2.96), TSH >4.5 mIU/L (OR: 6.54) had higher risk for malignancy than those with a TSH value of ≤0.4 mIU/L. Thyroid nodules with sizes of 1 to 1.9 cm (OR: 1.12), 2 to 2.9 cm (OR: 0.74), 3-3.9 cm (OR: 1.21), and ≥4 cm (OR: 0.52) were found to have no association with the risk of malignancy. Compared with TI-RADS 2 patients, those with categories 4B (OR: 1.35) and 5 (OR: 2.3) were found to be at higher risk of malignancy. Similarly, Bethesda IV (OR: 2.72), V (OR: 8.47), and VI (OR: 20; P < .02) category patients had a higher risk for malignancy than those in Bethesda class I. Among the study population, the papillary thyroid carcinoma was the most common type of thyroid cancer (86, 90.5%) followed by 7.4% (n = 7) of follicular thyroid carcinoma, 1.05% (n = 1) of anaplastic carcinoma, and 1.05% (n = 1) of medullary thyroid carcinoma.Conclusions:A predictive model for risk of malignancy using a combining characteristic of the TSH, US, and cytological classification systems could assist the clinicians in minimizing exposing the patients with TNs to nonessential invasive procedures.