Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by defective skin barrier function. Recent studies have identified mutations in the filaggrin gene, which encodes a key protein in skin barrier formation, as a risk factor for AD. This study investigated whether reduced filaggrin expression occurs in AD patients without known filaggrin mutations and whether the atopic inflammatory response modulates filaggrin expression. Skin biopsies and cultured keratinocytes were analyzed for filaggrin expression using real-time RT-PCR and immunohistochemistry. Filaggrin loss-of-function mutations were screened in 69 subjects. Results showed significantly reduced filaggrin expression in acute AD skin compared to normal skin, with further reduction in three European American AD patients heterozygous for the 2282del4 mutation. AD skin exhibited over-expression of IL-4 and IL-13, which significantly reduced filaggrin gene expression in keratinocytes. These findings suggest that AD patients have an acquired defect in filaggrin expression modulated by the atopic inflammatory response. The atopic immune response contributes to the skin barrier defect in AD, and neutralizing IL-4 and IL-13 may improve skin barrier integrity. Filaggrin is critical for the formation of the cornified cell envelope, and its deficiency is associated with impaired skin barrier function and increased risk of asthma in AD patients. This study highlights the role of Th2 cytokines in modulating filaggrin expression and suggests that the atopic immune response may contribute to the development of AD and its complications. The findings have important implications for the treatment of AD, emphasizing the need to target the inflammatory response to improve skin barrier function.Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by defective skin barrier function. Recent studies have identified mutations in the filaggrin gene, which encodes a key protein in skin barrier formation, as a risk factor for AD. This study investigated whether reduced filaggrin expression occurs in AD patients without known filaggrin mutations and whether the atopic inflammatory response modulates filaggrin expression. Skin biopsies and cultured keratinocytes were analyzed for filaggrin expression using real-time RT-PCR and immunohistochemistry. Filaggrin loss-of-function mutations were screened in 69 subjects. Results showed significantly reduced filaggrin expression in acute AD skin compared to normal skin, with further reduction in three European American AD patients heterozygous for the 2282del4 mutation. AD skin exhibited over-expression of IL-4 and IL-13, which significantly reduced filaggrin gene expression in keratinocytes. These findings suggest that AD patients have an acquired defect in filaggrin expression modulated by the atopic inflammatory response. The atopic immune response contributes to the skin barrier defect in AD, and neutralizing IL-4 and IL-13 may improve skin barrier integrity. Filaggrin is critical for the formation of the cornified cell envelope, and its deficiency is associated with impaired skin barrier function and increased risk of asthma in AD patients. This study highlights the role of Th2 cytokines in modulating filaggrin expression and suggests that the atopic immune response may contribute to the development of AD and its complications. The findings have important implications for the treatment of AD, emphasizing the need to target the inflammatory response to improve skin barrier function.