Keratinocytes play a key role in innate immune responses of the skin to bacterial and viral pathogens. Viral double-stranded RNA and its synthetic analogue polyriboinosinic-polyribocytidylic acid (poly-IC) are recognized via multiple pathways involving the receptors Toll-like receptor 3 (TLR3), protein kinase R (PKR), and the recently described cytosolic RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We show that preincubation of human keratinocytes with IFN-α enhances the proinflammatory responses to poly-IC. Kinetic studies suggest that this is mediated via upregulation of the receptors TLR3, PKR, RIG-I, and MDA5. Interestingly, expression of RIG-I, MDA5, and PKR was significantly increased in lesional skin from patients with psoriasis, a chronic inflammatory skin disease that is characterized by high IFN-α levels. These results suggest that psoriatic keratinocytes show increased sensitivity to viral RNA intermediates, thereby leading to excessive proinflammatory responses and maintenance of the inflammatory skin phenotype. Here, we provide early evidence that point toward a role for the recently described cytosolic innate RNA receptors in non-viral chronic inflammatory diseases.