There has been much recent investigation of the cyclooxygenase (Cox) enzymes in tumor biology, but, to our knowledge, no study has yet been published describing Cox activity in medullary carcinoma of the thyroid (MTC). Nine cases of MTC from the past 10 yr were retrieved from our hospital archives. Slides cut from formalin-fixed paraffin-embedded tumor tissue from these cases were assessed for the activities of Cox-1 and Cox-2 enzymes by immunohistochemistry as well as by a battery of immunohistochemical stains for intermediate filaments, peptide hormone, and proliferation and promoter antigens. The staining reactions were semiquantitatively assessed and scored for comparison with each other as well as with each patient s clinical presentation and course. Staining for Cox-1 and Cox-2 enzymes was present only in tumorous tissue, not in nontumorous thyroid tissue or C-cells. Cox-2 staining was not consistently increased over Cox-1 staining; however, Cox-2 staining bore statistically significant correlations with the expression of low molecular weight keratin, thyroid-transforming factor-1, topoisomerase, and MIB1. Hyperplastic C-cells from patients with diverse physiologic conditions and from three patients with C-cell hyperplasia accompanying medullary carcinoma or multiple endocrine neoplasia type IIa showed no reactivity for the Cox antibodies. It appears that Cox enzyme immunoreactivity is present only in the neoplastic C-cells of medullary carcinoma, but with variable expression. A practical application of the preceding finding might involve the use of Cox staining to distinguish invasive medullary carcinoma cells from hyperplastic C-cells.