The expression of peroxisome proliferator-activated receptor (PPAR)gamma in thyroid neoplasias and in normal thyroid (NT) tissues has not been fully investigated. The objectives of the present work were: to study and compare the relative expression of PPARgamma in normal, benign and malignant thyroid tissues and to correlate PPARgamma immunostaining with clinical/pathological features of patients with thyroid cancer. We analysed the expression of PPARgamma in several types of thyroid tissues by reverse transcription-polymerase chain reaction (RT-PCR), interphase fluorescent in situ hybridisation, real-time RT-PCR and immunohistochemistry. We have demonstrated that NT tissues express PPARgamma both at mRNA and at protein level. PAX8-PPARgamma fusion gene expression was found in 25% (six of 24) of follicular thyroid carcinomas (FTCs) and in 17% (six of 36) of follicular thyroid adenomas, but in none of the 10 normal tissues, 28 nodular hyperplasias, 38 papillary thyroid carcinomas (PTCs) and 11 poorly differentiated thyroid carcinomas (PDTCs). By real-time RT-PCR, we observed that tumours negative for the PAX8-PPARgamma rearrangement expressed lower levels of PPARgamma mRNA than the NT. Overexpression of PPARgamma transcripts was detected in 80% (four of five) of translocation-positive tumours. Diffuse nuclear staining was significantly (P<0.05) less prevalent in FTCs (53%; 18 of 34), PTCs (49%; 19 of 39) and PDTCs (0%; zero of 13) than in normal tissue (77%; 36 of 47). Peroxisome proliferator-activated receptorgamma-negative FTCs were more likely to be locally invasive, to persist after surgery, to metastasise and to have poorly differentiated areas. Papillary thyroid carcinomas with a predominantly follicular pattern were more often PPARgamma negative than classic PTCs (80% vs 28%; P=0.01). Our results demonstrated that PPARgamma is underexpressed in translocation-negative thyroid tumours of follicular origin and that a further reduction of PPARgamma expression is associated with dedifferentiation at later stages of tumour development and progression.