Psoriasis vulgaris is characterized by hyperproliferation and incomplete terminal differentiation of epidermal keratinocytes. Despite the established role of Wnt pathways in the regulation of stem cell proliferation and differentiation, they have not yet been associated with the pathophysiology of psoriasis. Here, we took biopsies from uninvolved and from lesional skin of 20 patients with plaque-type psoriasis. The biopsies were used for microarray RNA expression profiling. Based on paired samples from 13 patients, we defined 179 genes that were more than 2-fold differentially expressed in lesional skin. This list included 16 genes with known or possible association to the canonical Wnt/beta-catenin or the non-canonical Wnt/Ca2+ pathway. The expression of Wnt5a was 4-fold higher in lesional skin. Other Wnt molecules were largely unchanged (Wnt4 and Wnt16), or tended to be expressed at lower levels (Wnt7b). The mRNA expression levels of two inhibitory factors related to Wnt signaling, frizzled-related protein, and dickkopf homolog 2, were reduced in lesional skin, as was mRNA expression of cyclin D1. These findings were confirmed by quantitative reverse transcription-PCR experiments. We conclude that Wnt5a and other Wnt pathway genes are differentially expressed in psoriatic plaques. Their functional contribution to the pathophysiology of psoriasis needs to be elaborated.