Systemic sclerosis (SSc), an autoimmune disease, has endothelial dysfunction and tissue fibrosis. The lack of its specific activity markers urges the research. Endocan is an immunomodulatory protein associated with endothelial dysfunction. We aimed to measure of the endocan level in Systemic Sclerosis (SSc) patients’ sera to test its sensitivity to incidence, disease activity and treatment responses. Also, to evaluate its specificity by comparing these data with Behçet’s disease (BD) and rheumatoid arthritis (RA) patients’ data. Fifteen SSc, 15 BD, 30 RA patients, and 30 healthy individuals served as control. Diseases’ activity was evaluated. Venous blood samples were taken for complete blood count, erythrocyte sedimentation rate, C-reactive protein, kidney function, liver function, rheumatoid factor, ANA, anti-scl-70, C3, C4, and endocan serum level. The serum endocan level was determined by enzyme-linked immunosorbent assay.