Objective. Primary Sjögren's syndrome (SS) shares clinical and serologic features with rheumatoid arthritis and systemic lupus erythematosus, 2 diseases characterized by acceleration of atherosclerosis. Signs of precocious atherosclerosis have also been shown in SS, although the pathogenic basis of early arterial damage is unclear. The arterial wall was functionally evaluated in SS subjects with analysis of the role played by disease-related factors. Methods. Endothelium-dependent flow-mediated vasodilation (FMV) and endothelium-independent nitrate-mediated vasodilation (NMV) were evaluated in 45 women with SS and 59 age-matched female controls. In addition, serum soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1 (VCAM-1), and nitrotyrosine were detected. Results. Although patient FMV values did not differ from those of control subjects (mean ± SD 7.4 ± 3.6 versus 7.7 ± 1.9; not significant), NMV was lower in SS patients than in controls (mean ± SD 8.1 ± 3.5 versus 10.3 ± 2.1; P ≤ 0.001). Patient NMV was inversely correlated with soluble VCAM-1 levels (r = -0.38, P = 0.001) and directly correlated with leukocyte count (r = 0.26, P = 0.03). An NMV decrease was confirmed in SS patient subsets with evidence of leukopenia, rheumatoid factor, anti-SSB antibodies, and joint involvement. However, patients with joint involvement or parotid enlargement, 2 of the sites mainly affected by chronic inflammation in SS, had an FMV lower than controls and patients without these clinical features. Conclusion. Our results suggest that a functional impairment of the arterial wall may sustain early phases of atherosclerotic damage in SS. A combined effect of disease-related chronic inflammatory and immunologic factors appears to support dysfunction of endothelium and vascular smooth muscle cells, respectively.