Purpose: To evaluate the usefulness of multi-slice computed tomography (MSCT) in comparison with ultrasonography (US) for the differentiation of benign from malignant thyroid nodules and the evaluation of tumor extension. Materials and Methods: Thirty patients with thyroid nodules (14 malignant, 16 benign) who underwent both MSCT and US participated in the present study. MSCT with contrast enhancement was performed, and 3D shaded volume rendering (SVR) and multiplanar reconstruction (MPR) were employed to differentiate benign from malignant nodules and to evaluate tumor extension. US images were obtained using a 7.5 MHz annular array probe. A three-point rating scale was used for image interpretation, and the kappa statistic was employed to evaluate agreement between MSCT and US. Results: Sensitivity in differentiating benign from malignant nodules was found to be 85.7% for US and 78.6% for MSCT. Disagreement between MSCT and US occurred in assessing the homogeneity of the solid component and the presence of fibrous capsule. In two of seven T4 cases, MPR provided a more accurate diagnosis than US examination in detecting extracapsular invasion. Conclusion: For differential diagnosis of thyroid nodules, US was found to be better than MSCT. However, MSCT could be useful for the evaluation of advanced cases with suspicion of extracapsular extension.