Previous studies have demonstrated the utility of immunohistochemical staining for high-molecular-weight cytokeratins in the distinction of papillary carcinoma from other neoplasms of the thyroid, however, this technique was reliable only when applied to frozen tissues. Our objective in this study was to evaluate the use of this antibody in diagnostic thyroid pathology using paraffin-embedded materials with microwave antigen retrieval. We studied 89 thyroid tumors including 45 papillary carcinomas, 28 nodular hyperplasias, 10 follicular adenomas, and 6 follicular carcinomas. Moderate-to-strong diffuse staining was confined to papillary carcinoma, whereas follicular neoplasms and hyperplastic nodules were either negative or showed focal staining. These results confirm the utility of high-molecular-weight cytokeratins immunostaining in diagnostic thyroid pathology, and obviate the need for frozen material to apply this method. As paraffin-embedded tissues are more readily available, we recommend the use of high-molecular-weight cytokeratins with microwave antigen retrieval in cases in which it is difficult to distinguish papillary carcinoma from other thyroid tumors.