Syndecan-1 is a member of the transmembrane heparan sulfate proteoglycan family, whose membrane-bound and soluble forms are involved in wound healing, inflammation and vascular biology. Because these physiological events are implicated in the pathogenesis of systemic sclerosis (SSc), we investigated the clinical association of serum syndecan-1 levels in this disease. Serum syndecan-1 levels were significantly higher in SSc patients, both in diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc), than in healthy individuals, while comparable between dcSSc and lcSSc groups. In late stage dcSSc patients (disease duration of >6 years), but not non-late stage dcSSc patients (≤6 years), serum syndecan-1 levels were significantly higher than in normal controls. More importantly, SSc patients with elevated serum syndecan-1 levels had higher prevalence of telangiectasia, elevated right ventricular systolic pressure and decreased diffuse capacity of the lung for carbon monoxide than those with normal levels. Therefore, soluble syndecan-1 may be related to the development of proliferative vasculopathy in SSc patients.