In thyroid tumors, several cell cycle regulators have been found to be altered or overexpressed, but no data exist on E2F transcription factors. Such factors (E2F-1 in particular) act as the final effectors in the retinoblastoma pathway but are also involved in apoptosis. To analyze E2F-1 expression in thyroid neoplasms, we investigated 73 thyroid tumors, including 28 oxyphilic and 45 nonoxyphilic lesions, by immunohistochemistry, in parallel with other cell cycle-related proteins (p27, pRb, p53, and Ki67). p27, Ki-67, pRb, and p53 expression patterns generally overlapped the literature data. E2F-1 was expressed in all thyroid tumor types, both benign and malignant, with no statistical correlation with proliferative status (except for anaplastic carcinoma). A significantly higher percentage of tumor cells expressed E2F-1 in oxyphilic adenomas (71.5%) and oxyphilic carcinomas (66.1%) as compared with that of the corresponding nonoxyphilic lesions (30.8% and 34.5%, respectively; P < .05). These same tumors had a relatively low proliferative index. Therefore, because oxyphilic tumors of the thyroid show peculiar morphological, phenotypic, and ultrastructural features, possibly related to their particular metabolic conditions, it is possible that E2F-1 overexpression is linked to activities other than cell cycle entry in oxyphilic tumors. In conclusion, E2F-1 is expressed in both benign and malignant thyroid tumors, thus suggesting a wide involvement of the retinoblastoma pathway in thyroid tumorigenesis. In addition, in oxyphilic tumors, more than two thirds of tumor cells express E2F-1, an event possibly linked to proapoptotic rather than proliferative signals in such neoplasms.