Epidermal keratinocytes can counteract the detrimental effects of IFN-γ by inducing the expression of suppressor of cytokine signaling (SOCS) 1, which plays an important anti-inflammatory and self-protective role. To date, limited information exists on its expression and regulation in human diseased keratinocytes. In this study, we compared the expression levels of SOCS1 in keratinocytes isolated from skin affected by psoriasis with cells obtained from healthy donors, unveiling that keratinocytes are more prone than healthy cells to upregulate SOCS1 mRNA expression in response to IFN-γ. We explored the regulatory mechanisms involved in socs1 gene transcription, and found that Sp1 and IFN regulatory factor-1 transcription factors are, respectively, responsible for the basal and IFN-γ–induced activity of human socs1 promoter. In parallel, we demonstrated that socs1 promoter is negatively regulated by two transcriptional repressors, namely, growth factor independence-1b and Krüppel-like factor 4, which tightly control SOCS1 transcription on IFN-γ stimulation. Interestingly, although the expression of Sp1 and IFN regulatory factor-1 activators of socs1 promoter is unaltered, growth factor independence-1b and Krüppel-like factor 4 are significantly reduced in psoriatic compared with healthy keratinocytes. This reduction and the consequent unbalanced binding of transcriptional activators and repressors to socs1 promoter after IFN-γ stimulation might be responsible for the enhanced expression of SOCS1 in psoriatic cells. We suggest that SOCS1 exaggerated upregulation in psoriatic keratinocytes could represent a mechanism through which these cells attempt to protect themselves from IFN-γ effects. However, the SOCS1 increased levels in psoriatic keratinocytes are not sufficient to completely inhibit the expression of proinflammatory genes.