Keratin 1 (KRT1) and its heterodimer partner keratin 10 (KRT10) are major constituents of the intermediate filament cytoskeleton in suprabasal epidermis. KRT1 mutations cause epidermolytic ichthyosis in humans, characterized by loss of barrier integrity and recurrent erythema. In search of the largely unknown pathomechanisms and the role of keratins in barrier formation and inflammation control, we show here that Krt1 is crucial for maintenance of skin integrity and participates in an inflammatory network in murine keratinocytes. Absence of Krt1 caused a prenatal increase in interleukin-18 (IL-18) and S100A8/A9, accompanied by a barrier defect and perinatal lethality. Depletion of IL-18 partially rescued Krt1−/− mice. IL-18 release was keratinocyte-autonomous, KRT1- and caspase-1-dependent, supporting an upstream role of KRT1 in the pathology. Finally, transcriptome profiling revealed a Krt1-mediated gene expression signature similar to atopic eczema (AE) and psoriasis, but different from Krt5-deficiency and epidermolysis bullosa simplex (EBS). Our data suggest a functional link between KRT1 and human inflammatory skin diseases.