BACKGROUND: Parafibromin is a protein encoded by the HRPT2 oncosuppressor gene, and the expression is reported to be decreased or absent in parathyroid carcinomas. METHODS: A total of 26 tumor specimens from 18 patients with adenoma and 8 patients with carcinoma were immune-stained with an antibody against parafibromin. RESULTS: Parafibromin immunostaining showed strong positivity in 17 of 18 adenomas. Negative staining was noted in 3 of 8 carcinomas, and weak positivity was found in 3 of 8 carcinomas. The remaining 2 cases of carcinoma showed strong positivity. The loss of parafibromin expression (negative or weak positivity) demonstrated 94.4% specificity in the diagnosis of parathyroid carcinomas. Relapses or distant metastases of carcinoma occurred only in cases in which there was a loss of parafibromin immunostaining. CONCLUSIONS: Loss of parafibromin immunostating showed promising results in the differential diagnosis of parathyroid carcinoma from adenoma and may also serve as a prognostic marker. © 2011 Wiley Periodicals, Inc. Head Neck, 2011.