OBJECTIVE Osteopontin (OPN) is a multifunctional molecule highly expressed in chronic inflammatory and autoimmune diseases. We aimed to assess the plasma OPN levels in Behcet's disease (BD) patients and identify potential associations between these levels with disease activity, severity and clinical manifestations with special emphasis on vascular affection. METHODS We studied 55 BD patients and 31 age- and gender-matched healthy controls. Demographic, clinical and serological data were prospectively assessed. Activity and severity of BD were assessed using clinical scores and laboratory parameters. Plasma OPN levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS Plasma OPN levels were significantly higher in patients with BD compared to healthy controls (p < 0.000). The means for plasma OPN levels in active and inactive BD patients were significantly higher than that for the normal controls (with p < 0.000 and p = 0.002 respectively). The mean OPN levels significantly associated with the BD clinical severity score from mild to severe (p = 0.011). BD patients with vascular involvement had significant elevation of plasma OPN levels than those without (P = 0.03). OPN levels positively correlated with severity score, IL6, hsCRP, ESR, leucocytes count and neutrophil count. CONCLUSIONS Plasma OPN levels were higher in BD patients than in healthy controls and were found to be associated with disease activity, severity and vascular involvement. To confirm our results we propose that larger scale, multicentre studies with longer evaluation periods are needed.