Using different diagnostic strategies including cytology, IHC, and molecular genetic analysis, we were able to render a definitive diagnosis of an unusual and very infrequent case of metastatic papillary thyroid carcinoma in pleural effusion, which showed a marked papillary neoplastic structure characterized by positive expression of specific pathological markers such as CK-7 and TTF-1. This evidence concerns the gene TTF1 and differentiated thyroid carcinoma.