Hashimoto's thyroiditis is the most frequent autoimmune disorder, characterized by the presence of a large lymphocytic infiltration and secretion of inflammatory cytokines in the thyroid. Infiltrating lymphocytes and cytokines play a pivotal role in the progression of HT, characterized by the progressive destruction of the normal follicular architecture of the gland and death of follicular cells, ending with loss of thyroid function. Integrins are plasma membrane receptors for the cell-extra-cellular matrix components, with both structural and signaling functions. Integrin-mediated fibronectin (FN) binding is necessary for the correct function and survival of thyroid follicular cells. The purpose of this study was to determine the effect of interferon-γ (IFN-γ) stimulation on integrin expression and signaling in the thyroid cell. Cytotoxicity, integrin expression, cell adhesion to FN, and FN-stimulated ERK and AKT phosphorylation were determined in a normal human thyroid cell line treated with IFN-γ. IFN-γ induced apoptosis and reduced the expression of the integrin αvβ3. Integrin-mediated cell adhesion to FN was strongly impaired. Similarly, FN-stimulated ERK and AKT phosphorylation were inhibited. In conclusion, our study in a thyroid cell model demonstrates that IFN-γ induces apoptosis and inhibits the expression of the integrin αvβ3, reducing cell adhesion to FN and the succeeding outside-in signaling. These results suggest that integrins mediate the cytotoxic effect of IFN-γ and are involved in the destructive mechanism of autoimmune thyroiditis.