The pathologic diagnosis of thyroid tumors is often difficult and subjective. Immunohistochemical markers including high molecular weight cytokeratin (HMW-CK), cytokeratin-19 (CK-19) and epithelial membrane antigen have been suggested to be helpful in the distinction of various types of thyroid neoplasia. We collected frozen and/or paraffin-embedded tissues from a total of 116 surgically resected thyroids including 31 nodular hyperplasias, 18 follicular adenomas, 48 papillary carcinomas and 19 follicular carcinomas, stained them for HMW-CK, CK-19 and epithelial membrane antigen, and graded the results on a scale from 0 to 3+. Although little staining for HMW-CK was seen in paraffin-embedded tissues, different results were obtained when both HMW-CK and CK-19 were tested on frozen tissues. In papillary carcinomas, including the follicular variant of papillary carcinoma, diffuse positivity for these antigens was seen immunohistochemically, and these antigens significantly distinguished papillary carcinomas from follicular neoplasms and nodular hyperplasias. Focal staining for epithelial membrane antigen was found in all pathological processes; thus this marker was not useful. We conclude that HMW-CK and CK-19 are useful in the distinction of papillary carcinomas from follicular adenomas, follicular carcinomas, and nodular hyperplasias when applied to frozen tissues. We recommend that samples of thyroid follicular nodules be frozen, and retrieved if necessary to aid in the differential diagnosis of these tumors.