BACKGROUND:The aims of this study were to analyze cytomorphological features of Tripath PREP (BD SurePath, Burlington, NC) preparations in thyroid nodules and to examine adequacy and accuracy of SurePath and frozen sections for both clinical outcome and histological diagnosis when applicable.METHODS:Gathered during a period of 4 years, 712 SurePath specimens of the thyroid were included. Histological (n = 207) or clinical follow‐up (n = 505) was available in all cases. During the same period, 253 frozen sections of surgical thyroid resection specimens were also assessed. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were calculated.RESULTS:Sensitivity was 77% for SurePath and 29% for frozen section; specificity was 81% for SurePath and 100% for frozen section; accuracy was 80% for SurePath and 90% for frozen section. One hundred seventy‐eight (25%) SurePath patients were considered unsatisfactory for diagnosis. In this study, sensitivity, specificity, and accuracy were comparable for SurePath and other reported results of liquid‐based thyroid cytology. Presence of free colloid or pure cystic changes favored a benign diagnosis. Cellular smears with nuclear atypia of papillary carcinoma allowed an overt diagnosis of malignancy.CONCLUSIONS:The authors concluded that SurePath is a reliable technique for assessment of thyroid nodules and offers the advantage of easy identification of colloid and atypical nuclei. Supplementary frozen section analysis should be limited to an FNAC diagnosis of suspicious for papillary carcinoma. Cancer (Cancer Cytopathol) 2011. © 2010 American Cancer Society.