Objectives: The main goal of our study was to investigate the possible involvement of TNF family cytokines TRAIL and TWEAK in the pathogenesis of psoriasis. Therefore, we aimed to explore the expression patterns of TRAIL, TWEAK and their respective receptors in the skin of patients with psoriasis and to detect their presence among different populations of cells comprising the psoriatic inflammatory infiltrate. In addition, we aimed to investigate possible association of TWEAK with altered proliferation and differentiation of keratinocytes in psoriasis. Material and Methods: Immunohistochemistry for TRAIL, TWEAK and receptors DR4, DR5, DcR1, DcR2 and Fn14 was performed on samples of healthy skin as well as lesional and non-lesional skin from psoriatic patients. Phenotype of cells that express the examined cytokines and receptors was examined by means of double immunofluorescence staining and co-localisation analysis with cell surface markers CD4, CD8, CD11c and CD68. To investigate the involvement of TWEAK in proliferation and differentiation of keratinocytes, we explored its co- expression with Proliferating Cell Nuclear Antigen (PCNA) and keratin K10. Results: Immunohistochemical expression of TRAIL and its receptors DR5 and DcR2 is sigificantly increased in the epidermis of lesional psoriatic skin when compared to the epidermis of healthy skin. In addition, significantly increased expression of TRAIL is present already in the non-lesional skin of patients with psoriasis. In the dermis, TRAIL is readily expressed by all of the examined cell populations in the psoriatic inflammatory infiltrate, receptors DR5 and DcR2 are expressed by CD68+ macrophages and endothelial cells whereas receptor DcR1 is present exclusively in neutrophils. Membranous expression of receptor DR4 was not detected within dermal cells. Cytokine TWEAK is expressed in the suprabasal epidermal layers of healthy skin as well as non-lesional and lesional skin of patients with psoriasis. However, its expression is significantly decreased in the lesional psoriatic epidermis. Cells of the inflammatory infiltrate do not express TWEAK or its receptor Fn14. Epidermal expression of TWEAK depends on the proliferative rate and differentiation of keratinocytes in a way that these are either TWEAK+/K10+ or TWEAK-/PCNA+. Conclusion: According to our findings on the increased expression of TRAIL in the epidermis of patients with psoriasis as well as its widespread expression within cells of the inflammatory infiltrate, it seems that this cytokine possesses multiple roles in the pathogenesis of psoriasis. On the other hand, cytokine TWEAK is probably associated with altered growth and differentiation of keratinocytes in psoriasis.