PURPOSE To prospectively evaluate the elastographic appearance of thyroid gland tumors and explore the potential sensitivity and specificity of ultrasonographic (US) elastography for differentiating benign and malignant tumors, with histopathologic analysis as the reference standard. MATERIALS AND METHODS The study was institutional review board approved, and each patient gave written informed consent. Fifty-two thyroid gland lesions (22 malignant, 30 benign) in 31 consecutive patients (six men, 25 women; mean age, 49.7 years +/- 14.7 [standard deviation]) were examined with real-time elastography in the elasticity imaging mode implemented on a clinical US scanner modified for research. In addition, the radiofrequency echo data stored during US were exported from the scanner and used for off-line strain image reconstruction. All elastograms were evaluated for the lesion visibility, relative brightness, and margin regularity and definition by using a four-point scale. In addition, normal thyroid gland tissue and thyroid gland tumor strains were measured on off-line processed elastograms, and the thyroid gland-to-tumor strain ratio (ie, strain index) was calculated. The potential of elastographic criteria for the diagnosis of thyroid gland cancer was evaluated with univariate analysis and multivariate logistic regression. Qualitative variables were compared by using the chi2 test, and quantitative variables were compared by using the Mann-Whitney U test. P < .05 was considered to indicate significance. RESULTS A strain index value greater than 4 on off-line processed elastograms was the strongest independent predictor of thyroid gland malignancy (P < .001); this criterion had 96% specificity and 82% sensitivity. Two other elastographic criteria, which were evaluated on real-time elastograms--a margin regularity score higher than 3 (88% specificity, 36% sensitivity) and a tumor area ratio higher than 1 (92% specificity, 46% sensitivity)--also were associated with malignancy (P < .05). However, the usefulness of these criteria was not considered to be high because of their low sensitivity. CONCLUSION Elastography is a promising imaging technique that can assist in the differential diagnosis of thyroid cancer.