Background: Psoriasis is a chronic-relapsing inflammatory skin disorder, in whose pathogenesis oxidative stress is suggested to be involved. Among different enzymes that play a role in maintaining the cellular redox balance, we aimed to assess the alteration of glutathione peroxidase (GPX) activity in cutaneous lesions and its correlation with the disease severity, firstly, to support the possible candidacy of this enzyme for future topical therapeutic regimens, and secondly, to move forward in understanding the etiology of the disease and the pathogenic mechanisms involved in cutaneous lesions so as to pave the way for further investigations. Methods: The clinical severity of disease was determined according to Psoriasis Area and Severity Index (PASI) scoring system. The level of GPX activity in the skin biopsies from 20 psoriatic patients was measured using Cayman’s glutathione peroxidase assay kit, and its association with disease severity was assessed in each patient. Results: Tissue GPX activity was significantly higher in patients with mild psoriasis (149.02 ± 24.213 nmol/min/ml) compared to patients with moderate psoriasis (120.58±21.038 nmol/min/ ml) (p-value < 0.05). There was a significant negative correlation between the activity of GPX and each PASI-associated criterion, including redness, scaling and thickness. Among all the criteria of PASI, scaling was independently correlated with the activity of GPX (p-value < 0.05). Conclusion: The reduced activity of GPX in dermal lesions might be associated with the disease pathogenesis, having a valuable role in diagnosis and therapy.