We prospectively studied 26 patients with cold thyroid nodules (five malignant and 21 benign nodules) on Tc-99m pertechnetate scintigraphy to investigate the diagnostic value of Tc-99m tetrofosmin scintigraphy and color-Doppler sonography in differentiating malignant from benign thyroid nodules. In each patient, Tc-99m Tetrofosmin uptake in the nodule and intranodule vascularity were assessed semiquantatively. Both the uptake and vascularity were classified as low, Iso or high. Eight out of 26 nodules showed high Tc-99m tetrofosmin uptake; five of them were malignant. Eight (including four malignant tumors) out of 26 nodules showed increased vascularity compared with normal thyroid tissue on color-Doppler sonography. In six out of eight patients with high uptake of Tc99m-tetrofosmin, increased vascularity was observed. The sensitivity, specificity, negative predictive value, and positive predictive value of Tc-99m tetrofosmin scintigraphy and color-Doppler sonography were determined to be 100% and 80%, 85% and 80%, 62% and 50%, and 100% and 94%, respectively. We conclude that color-Doppler sonography seems to have limited value in the detection of malignant thyroid nodules. However, Tc-99m tetrofosmin scintigraphy is a sensitive method to use in diagnosing malignant nodules, although it is not specific for the detection of malignant nodules.