LDL particles must be modified in the arterial wall to be taken up by macrophages at an excessive rate, leading to foam cell formation. Phospholipase A₂ (PLA₂) has been shown to modify LDL particles in vitro by degrading its phospholipids, resulting in enhanced uptake by macrophages. Reaction products of PLA₂ are lysophospholipids and nonesterified fatty acids (mainly arachidonic acid), which are precursors of potent inflammatory mediators and which have been found in atherosclerotic regions of the arterial wall. To elucidate the expression of PLA₂ in normal and diseased arteries, frozen tissue sections of human nonatherosclerotic mesenteric artery and carotid plaques were examined by immunohistochemistry using specific antibodies against secretory PLA₂ types I and II and cytosolic PLA₂ (85 kd). Secretory PLA₂ type I was not detected. High expression of secretory PLA₂ type II was found throughout the media in both normal and atherosclerotic artery specimens, in which smooth muscle cells dominated. Cytosolic PLA₂ was found exclusively in diseased artery, mainly in the intima in regions with an inflammatory infiltrate consisting of macrophages and smooth muscle cells. Furthermore, both normal and atherosclerotic artery possessed substantial PLA₂ activity. It is suggested that secretory PLA₂ type II could play an important role in early atherogenesis because it is present in the preatherosclerotic arterial wall, where it may lead to LDL modification, foam cell formation, and activation of immune mechanisms.