Background: Although it is now considered a prototypic Th1/Th17-mediated disease, several gaps still exist in our understanding of the pathogenesis of psoriasis. Sirtuins, a family of seven proteins that have generated huge interest in several fields including dermatology, have been proposed to contribute to the development of inflammatory and hyperproliferative disease. It has been proposed that changes in Sirtuin 1 (SIRT1), through its effect on pro-inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α), may contribute to the development of the psoriatic plaque. Objective: Our aim was to study the degree of expression of Sirtuin 1 (SIRT1) and its relation to clinical disease parameters as well as its interactions with Tumor Necrosis Factor-alpha (TNF-α) in psoriatic skin.Methods: 30 psoriatic patients and 22 age, sex and skin type matched controls were included. Full clinical examination was done and tissue levels of SIRT1 and TNF-α were measured by ELISA. Results: SIRT1 was significantly downregulated in lesional psoriatic skin in comparison to controls and non-lesional skin (p<0.001). TNF-α was significantly upregulated in lesional psoriatic skin in comparison to controls and non-lesional skin (p<0.001). A significant negative correlation between non-lesional TNF-α and disease duration, as well as a positive correlation between TNF-α and SIRT1 in non-lesional psoriatic skin (r= 0.451, p= 0.021) were detected. Limitations: Small sample size. Conclusion: Our study concludes that the downregulation of SIRT1 in psoriatic plaques is involved in the pathogenesis of psoriasis. This occurs through several mechanisms, including a possible unchecked pro-inflammatory TNF-α consequence.