BACKGROUND: Lp(a) (lipoprotein[a]) is associated with cardiovascular disease, but neither the causal nature nor the underlying mechanisms are fully documented. This study investigated whether Lp(a) triggers atherogenesis by dysregulating vascular redox–sensitive inflammatory state. METHODS: Plasma Lp(a) was measured in 1027 patients with advanced coronary artery disease undergoing cardiac surgery. These patients were genotyped, and a modified LPA genetic risk score (LPA GRS) determining Lp(a) levels was generated. RNA sequencing and vascular superoxide measurements were performed in internal mammary arteries, and the contribution of NOXs (NADPH oxidases) and uncoupled eNOS (endothelial nitric oxide synthase) was determined. The median follow-up was 5.07 years. RESULTS: Increased plasma Lp(a) ( P =0.03) and LPA GRS ( P =0.01) were associated with elevated arterial superoxide in the overall patient population, an effect that was driven by nondiabetics. This effect was primarily due to eNOS uncoupling via reduced vascular BH4 (tetrahydrobiopterin) bioavailability. There was no significant impact of Lp(a) variability on vascular NOX–derived superoxide ( P =0.13). RNA sequencing of arterial tissue revealed dysregulation of nitrosative and inflammatory signaling in high Lp(a) patients although there was no association with systemic biomarkers of inflammation (ie, hsCRP [high-sensitivity C-reactive protein]; P =0.82) or oxidative stress (ie, malondialdehyde; P =0.61). Finally, both LPA GRS (hazard ratio, 3.615 [95% CI, 1.044–12.515]; P =0.043) and high plasma Lp(a) (hazard ratio, 3.286 [95% CI, 1.003–10.767]; P =0.049) were associated with elevated risk for cardiac mortality. This association was vascular superoxide-dependent, implying that redox-sensitive inflammatory signaling may be a link between Lp(a) and cardiovascular risk. All the above associations were independent of plasma ApoB (apolipoprotein-B). CONCLUSIONS: This study demonstrates for the first time that a genetically determined increase in plasma Lp(a) results in dysregulated vascular redox/nitrosative signaling in patients with atherosclerosis.