Corneodesmosin (Cdsn) is a late differentiation epidermal glycoprotein putatively involved in keratinocyte adhesion. The Cdsn gene lies within the susceptibility region on chromosome 6p21.3 (PSORS1) for psoriasis, a common chronic disfiguring skin disease. A particular allelic variant of Cdsn has a strong association with psoriasis. Therefore, genetically and biologically, Cdsn is a possible candidate gene for psoriasis susceptibility. To investigate a potential role for Cdsn in psoriasis pathogenesis, protein expression studies were performed by quantitative immunohistochemistry on normal skin, psoriatic skin (lesional and nonlesional), and other skin disorders using monoclonal antibodies (G36-19 and F28-27). In normal and nonlesional skin, Cdsn was expressed in stratum corneum and one or two layers of superficial stratum granulosum. In lesional psoriasis, there was a significant increase in Cdsn expression, which was observed in multiple layers of stratum spinosum and in stratum corneum. The expression pattern varied from granular, cytoplasmic immunoreactivity to cell surface labeling with weakly immunoreactive cytoplasm. In chronic atopic dermatitis, lichen planus, mycosis fungoides, and pityriasis rubra pilaris, Cdsn immunoreactivity was confined to stratum corneum and upper stratum granulosum with no stratum spinosum immunoreactivity. Immunoelectron microscopy of normal and lesional psoriatic skin demonstrated Cdsn release concomitant with involucrin incorporation into cell envelopes and completed before mature envelope formation. Extracellular release of Cdsn occurred at a lower level of the epidermis in psoriasis than normal skin. These protein expression studies provide evidence of altered Cdsn expression in psoriasis consistent with a role of Cdsn in disease pathogenesis. Further functional and genetic studies of Cdsn are justified to determine its role as a potential psoriasis-susceptibility factor.