Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), also known as platelet-activating factor acetylhydrolase, is a plasma enzyme that circulates bound to lipoproteins. The association between Lp-PLA(2) and atherosclerosis is ambiguous, as it can both degrade and generate potentially damaging vasoactive molecules. In this article, we speculate that Lp-PLA(2) associated with HDL might have cardioprotective properties, whereas the same enzyme bound to LDL might contribute directly to atherosclerosis at all stages, from lipoprotein oxidation to endothelial dysfunction, and plaque initiation and growth. Genetic and animal model studies give varying indications as to the contribution of Lp-PLA(2) to atherogenesis and tend to support the view that higher Lp-PLA(2) levels are cardioprotective. By contrast, a series of population studies point clearly to a positive association between plasma Lp-PLA(2) levels or activity levels and risk of coronary heart disease or stroke. Typically, people with Lp-PLA(2) levels in the highest quintile of the population have about a twofold greater risk than those in the lowest quintile. It is, perhaps, too early to introduce Lp-PLA(2) as a population-wide biomarker for coronary heart disease risk; however, with accumulating evidence, it might find a place in a stepwise risk assessment of individuals who require more aggressive intervention to prevent vascular disease.