Objective: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a lipoprotein-bound enzyme that can release atherogenic isoprostanes from esterified phospholipids and may be involved in inflammation and atherosclerosis. This study investigates the association between Lp-PLA2 activity and coronary artery disease (CAD) in relationship to oxidative stress markers, in particular urinary 8-epi-prostaglandin F2慣 (8-epi-PGF2慣). Methods: We conducted a case-control study in which the cross-sectional relationship between Lp-PLA2 activity, lipoproteins, and oxidative stress markers was determined in 799 patients with angiographically confirmed CAD and 925 healthy control subjects. Results: Lp-PLA2 activity was higher in CAD patients than in controls (32.9짹0.46 nmol/mL/min vs. 29.7짹0.42 nmol/mL/min; P<0.001). Both elevated Lp-PLA2 activity and urinary excretion of 8-epi-PGF2慣 levels were associated with increased risk of CAD (P for trend<0.001). Odds ratios for the upper quartiles of Lp-PLA2 activity and 8-epi-PGF2慣 concentration. were 2.47 (95% CI, 1.79, 3.40) and 2.19 (95% CI, 1.52, 3.15), respectively after adjustment for sex, age, BMI, blood pressure, smoking and drinking status, LDL-cholesterol, and HDL-cholesterol. When we examined the additive effect of both markers for CAD risk, the relationship between 8-epi-PGF2慣 and CAD was weakened above the second quartile of Lp-PLA2 activity. Furthermore, Lp-PLA2 activity was positively correlated with urinary excretion levels of 8-epi PGF2慣 both in controls (r=0.277, P<0.001) and CAD patients (r=0.202, P<0.001), and with the tail moment of lymphocyte DNA (r=0.213, P<0.001) in controls. Conclusions: This study demonstrates association of elevated Lp-PLA2 activity with CAD risk in relation to oxidant stress, supporting a pro-atherogenic role of Lp-PLA2.