The molecular genetics underlying thyroid carcinogenesis is not clear. Recent identification of a PAX8-peroxisome proliferator-activated receptor gamma (PPARgamma) fusion gene in human thyroid follicular carcinoma suggests a tumor suppressor role of PPARgamma in thyroid carcinogenesis. Mice harboring a knockin mutant thyroid hormone beta receptor (TRbetaPV) spontaneously develop thyroid follicular carcinoma through pathological progression of hyperplasia, capsular invasion, vascular invasion, anaplasia, and eventually, distant organ metastasis. This mutant mouse (TRbeta(PV/PV) mouse) provides an unusual opportunity to ascertain the role of PPARgamma in thyroid carcinogenesis. Here, we show that the expression of PPARgamma mRNA was repressed in the thyroid gland of mutant mice during carcinogenesis. In addition, TRbetaPV acted to abolish the ligand (troglitazone)-mediated transcriptional activity of PPARgamma. These results indicate that repression of PPARgamma expression and its transcriptional activity are associated with thyroid carcinogenesis and raise the possibility that PPARgamma could be tested as a therapeutic target in thyroid follicular carcinoma.