Cutaneous lupus erythematosus is a disfiguring and common manifestation in systemic lupus erythematosus, and the etiology of this predisposition for cutaneous inflammation is unknown. Here, we sought to examine the keratinocyte as an important source of IL-6 and define the mechanism for its increased production in cutaneous lupus erythematosus. Evaluation of discoid and subacute cutaneous lupus erythematosus lesions showed significant epidermal up-regulation of IL-6 compared with control via real-time PCR and immunohistochemistry. Keratinocytes from unaffected skin of lupus patients produced significantly more IL-6 compared with healthy control subjects after exposure to toll-like receptor 2, 3, or 4 agonists or exposure to UVB radiation. Pretreatment with type I interferons (IFN-α and IFN-κ) increased IL-6 production by control keratinocytes, and type I IFN blockade decreased IL-6 secretion by lupus keratinocytes. Secretion of keratinocyte-specific IFN-κ was significantly increased after toll-like receptor 2 and UVB treatment in lupus keratinocytes, and neutralization of IFN-κ decreased IL-6 production by lupus keratinocytes. Thus, lupus keratinocytes are primed for IL-6 hyperproduction in a type I IFN-dependent manner. Increased production of IFN-κ by lupus keratinocytes drives this response, indicating that IFN-κ may play a pathogenic role in cutaneous lupus erythematosus and serve as a target for treatment.