Background— To explore potential interrelationships between lipoprotein-associated phosholipase A2 (Lp-PLA₂)_, the metabolic syndrome (MetS), and incident cardiovascular disease (CVD).

Methods and Results— MetS was defined by the National Cholesterol Education Program Adult treatment Panel III criteria in 4480 nondiabetic Malmö Diet and Cancer Study subjects without history of CVD. Incidence of first CVD event (stroke [130 cases] or myocardial infarction [131]) was monitored over 10 years of follow-up. Lp-PLA₂ activity and mass were significantly higher in subjects with MetS. Lp-PLA₂ activity compared with Lp-PLA₂ mass was more strongly correlated to individual components and increased more linearly with number of MetS components. Elevated Lp-PLA₂ activity (top compared with bottom tertile), but not elevated Lp-PLA₂ mass, increased risk for incident CVD (relative risk, RR: 1.54, 95% CI 1.07 to 2.24), as did MetS (1.42, 1.06 to 1.90) after taking possible confounders into account. Relative to those without either elevated Lp-PLA₂ activity or MetS, combination of MetS and elevated Lp-PLA₂ activity increased risk for CVD (1.97, 1.34 to 2.90). Elevated Lp-PLA₂ activity without MetS increased risk for CVD (1.40, 1.03 to 1.92) but not MetS without elevated Lp-PLA₂ activity (1.46, 0.94 to 2.27).

Conclusion— Lp-PLA₂ is associated to the MetS. Higher plasma levels of Lp-PLA₂ increased risk for incident CVD regardless of MetS. The simultaneous presence of elevated Lp-PLA₂ activity and MetS may identify an especially high risk individual.