Arterial stiffness forms the basis of cardiovascular diseases (CVD) and is also an independent predictor of CVD risk. Early detection and intervention of arterial stiffness are important for improving the global burden of CVD. Pulse wave velocity (PWV) is the gold standard for assessing arterial stiffness and the molecular mechanism of arterial stiffness remains to be studied. Extracellular matrix (ECM) remodeling is one of the major mechanisms of arterial stiffness. Partial quantitative changes of ECM proteins can be detected in plasma. Therefore, we examined the hypothesis that a discovery proteomic comparison of plasma proteins between high arterial stiffness (baPWV >= 1,400 cm/s) and normal arterial stiffness (baPWV < 1,400 cm/s) populations might identify relevant changed ECM proteins for arterial stiffness. Plasma samples were randomly selected from normal arterial stiffness (n = 6) and high arterial stiffness (n = 6) people. Isobaric tags for relative and absolute quantitation (iTRAQ) based quantitative proteomics technique was performed to find a total of 169 differentially expressed proteins (DEPs). Nine ECM proteins were included in all DEPs and were all up-regulated proteins. Fibulin-1 had the highest statistically fold-change (FC = 3.7, p < 0.0001) in the high arterial stiffness population compared with the control group during the nine ECM proteins. The expression of plasma fibulin-1 in normal arterial stiffness (n = 112) and high arterial stiffness (n = 72) populations was confirmed through enzyme-linked immunosorbent assay (ELISA). Similarly, ELISA results showed that plasma concentrations of fibulin-1 in the high arterial stiffness group were higher than those in the normal arterial stiffness group (12.69 +/- 0.89 vs. 9.84 +/- 0.71 mu g/ml, p < 0.05). Univariate analysis of fibulin-1 with brachial-ankle pulse wave velocity (baPWV) indicated that fibulin-1 was positively correlated with baPWV in all participants (r = 0.32, p < 0.01) and a stronger positive correlation between baPWV and fibulin-1 in high arterial stiffness group (r = 0.64, p < 0.0001) was found. Multiple regression analysis of factors affecting baPWV showed that fibulin-1 was also a significant determinant of the increased ba-PWV (R-2 = 0.635, p = 0.001). Partial correlation analysis showed that baPWV increased with the growth of plasma fibulin-1(r = 0.267, p < 0.001). In conclusion, our results demonstrated that fibulin-1 is positively correlated with ba-PWV and an independent risk factor for arterial stiffness.