BACKGROUND: The relationship between cumulative non-high-density lipoprotein-cholesterol (cum-non-HDL-C) and the risk of new-onset arterial stiffness has not been characterized. METHODS AND RESULTS: A total of 6,852 participants with 3 consecutive measurements of total cholesterol and HDL-C and a baseline brachial-ankle pulse wave velocity (baPWV) <
1,400 cm/s during 2010-2011, 2012-2013, and 2014-2015 were included. The cum-non-HDL-C concentrations were determined using time weighting, and the participants were grouped: G1 <
130 mg/dL, G2 130-159 mg/dL, G3 160-189 mg/dL, and G4 ≥190 mg/dL. Cox models were used to characterize the relationships between cum-non-HDL-C and arterial stiffness by calculating hazard ratios (HRs) and 95% confidence intervals (CIs). Arterial stiffness (baPWV ≥1,800 cm/s) was present in 327 (4.77%) participants over a median follow-up period of 7.7 (interquartile range 7.2-8.2) years. After adjustment for multiple confounders, G2-4 had adjusted HRs (95% CIs) of 1.12 (0.85, 1.48), 1.45 (1.05, 1.99), and 2.52 (1.69, 3.74), respectively (P=0.0004), vs. G1. The adjusted HRs (95% CIs) for exposures of 2, 4, and 6 years were 1.17 (0.87, 1.58), 1.46 (1.96, 2.01), and 1.67 (1.14, 2.44), respectively (P=0.0029), vs. 0 years. Restricted cubic spline analysis revealed a linear dose-response relationship between cum-non-HDL-C and arterial stiffness risk. CONCLUSIONS: A high cum-non-HDL-C concentration and prolonged exposure to this increase the risk of arterial stiffness. The monitoring and maintenance of appropriate cum-non-HDL-C may reduce the risk of arterial stiffness.