BackgroundCurrently, no effective and reproducible imaging method can quantitatively differentiate between benign and malignant thyroid nodules. This study aimed to assess the role of diffusion-weighted imaging (DWI) in differentiating benign from malignant thyroid nodules. MethodologyWe conducted an observational study in the Department of Radiodiagnosis at R. L. Jalappa Hospital and Research Center, Kolar, India. The study was conducted from January 2020 to June 2021, among 43 patients with thyroid swelling or nodules. We recorded patient baseline data, pertinent clinical history, and relevant laboratory investigations. Patients underwent diffusion-weighted MRI of the neck. We used receiver operator curve analysis to determine the utility of the apparent diffusion coefficient (ADC) of the thyroid nodule in predicting the histopathological diagnosis. Data were analyzed using coGuide (V1.0.3, BDSS Corp., India). ResultsA total of 43 patients were enrolled in the study (35 women, 81.4%; 8 men, 18.6%). The mean (SD) age was 49.8 (14.3) years. Nodular hyperplasia was the most common histopathologic diagnosis of the nodule (25.5%), followed by lymphocytic thyroiditis (16.2%). The MRI and histopathological findings matched: both found 35 (81.4%) nodules as benign and 8 (18.6%) as malignant. The ADC value of thyroid nodules had excellent predictive validity in predicting malignancy, as indicated by the area under the curve of 0.925 (95% confidence interval [CI] 0.804-1.000; p < 0.001). The sensitivity was 87.50% (95% CI 47.35%-99.68%), specificity was 94.29% (95% CI 80.84%-99.30%), and the total diagnostic accuracy obtained was 93.02% (95% CI 80.94%-98.54%). ConclusionsDWI with ADC measurement has the potential to differentiate between benign and malignant thyroid nodules.