Psoriasis is a genetically determined inflammatory skin disease. Although the transition from uninvolved into lesional skin is accompanied by changes in the expression of multiple genes, much less is known about the difference between uninvolved skin from psoriatic patients as opposed to skin from normal individuals. Multiple biochemical and morphological changes were reported decades ago in uninvolved psoriatic skin but remain poorly understood. Here, we show dysregulation of 223 transcripts representing 179 unique genes in uninvolved psoriatic skin, 178 of which were not previously known to be altered in their expression. The proteins encoded by these transcripts are involved in lipid metabolism, antimicrobial defenses, epidermal differentiation, and control of cutaneous vasculature. Cluster analysis of transcripts with significantly altered expression identified a group of genes involved in lipid metabolism with highly correlated gene expression. Promoter analysis showed enrichment for binding sites of three transcription factors; peroxisome proliferator-activator receptor alpha (PPARA), sterol regulatory element-binding protein (SREBF), and estrogen receptor 2 (ESR2), suggesting that the coordinate regulation of lipid metabolic genes may be related to the action of these factors. Taken together, our results identify a "pre-psoriatic" gene expression signature, suggesting decreased lipid biosynthesis and increased innate immunity in uninvolved psoriatic skin.