Background: Psoriasis is a chronic inflammatory skin disorder with a complex pathogenesis. While the roles of immune cells and inflammatory mediators have been extensively studied, the involvement of extracellular matrix components, especially heparan sulfate and its degrading enzyme heparinase, has not been fully investigated. Given the enzyme's known functions in other autoimmune conditions, its potential role in psoriasis needs more investigation. Aim: This work aimed to assess the serum level of heparinase among psoriasis patients and its relationship with disease severity and activity. Methods: We carried out a case-control study involving 20 patients with plaque psoriasis and 20 healthy controls at the Dermatology Outpatient Clinic, Zagazig University. Patients underwent clinical assessments, including the Psoriasis Area and Severity Index (PASI), and serum heparinase levels were measured using an enzyme-linked immunosorbent assay (ELISA). Results: Psoriatic patients had significantly higher heparinase levels than the controls (P<0.001). Heparinase levels had a strong positive correlation with PASI scores (r=0.86, P<0.001). Stratified analysis revealed significantly elevated heparinase levels across severity groups (P<0.001). Conclusions: Heparinase is markedly upregulated in psoriasis and strongly correlates with disease severity. It could be a promising biomarker for diagnosing and monitoring disease activity. Further studies with larger populations are needed to validate these findings and explore their potential as a therapeutic target.