Recovery of p53 function in undifferentiated thyroid carcinoma cells carrying an altered p53 gene is able to modify cell tumorigenic properties. It is not known whether such an effect may also be achieved in thyroid cancer cells expressing wild-type p53, as in the majority of differentiated thyroid carcinomas. Effects of p53 transduction in a thyroid carcinoma cell line (FRO) exhibiting a wild-type endogenous p53 gene, in comparison to a cell line (WRO) exhibiting mutant p53, were investigated by using an inducible chimeric construct containing human p53 complementary DNA fused to the ligand binding domain of the estrogen receptor (p53ER). FRO cells were unaffected by exogenous p53 expression in terms of both proliferation and viability. On the contrary, p53 reexpression in WRO cells containing hemizygous mutated p53 allele caused a strong growth inhibition due to cell accumulation in the G1 phase of the cell cycle. In addition, exogenous p53 did not influence FRO cell behavior in response to TSH treatment or modify cell resistance to the chemotherapeutic agent, doxorubicin. Our results indicate that exogenous expression of wild-type p53 affects thyroid tumorigenic properties only in cells carrying an altered p53, whereas it is ineffective in cells expressing wild-type p53 activity. Therefore, the endogenous p53 status seems to be a major determinant for the effectiveness of a p53-based gene therapy for thyroid cancer.