We have conditionally inactivated the E-cadherin gene in the thyroid follicular cells of mouse embryo to unravel its role in thyroid development. We have used the Cre-loxP system in which the Cre-recombinase was expressed under the control of the tissue-specific thyroglobulin promoter that becomes active at E15. At postnatal day 7 thyroid follicle lumens in the knockout mice were about 30% smaller with respect to control mice and had an irregular shape. E-cadherin was almost completely absent in thyrocytes, -catenin was significantly reduced while no change in -catenin was detected. -catenin was also reduced on the cell plasma membrane. Despite the dramatic loss of E-cadherin and of -catenin, cell-cell junctions were not affected, the distribution of tight junction proteins was unaltered and no increase of thyroglobulin circulating in the blood was observed. In addition, we found that other members of the cadherin family, the R-cadherin and the Ksp-cadherin, were expressed in thyrocytes and that their membrane distribution was not altered in the E-cadherin conditional knockout mouse. Our results indicate that E-cadherin has a role in the development of the thyroid gland and in the expression of -catenin but it is not essential for the maintenance of follicular cell adhesion.