Lipoprotein metabolism is markedly altered during inflammation. The concentration of human secretory phospholipase A2 (sPLA2) can increase hundreds of fold in inflammatory fluids and in the circulation. It was detected in atherosclerotic lesions where many inflammatory genes are induced. As sPLA2 has been reported to act on lipoproteins as substrates, lipoprotein profiles in transgenic mice expressing sPLA2 were studied. HDL levels were markedly decreased in transgenic mice overexpressing sPLA2. HDL in the transgenics were smaller in size, with a significant decrease (11%) in phospholipid content compared to nontransgenic littermates. In sPLA2 transgenic mice and transgenic mice expressing both sPLA2 and human apolipoprotein B (apoB), the concentrations of apoB-containing lipoproteins were not altered. We conclude that sPLA2 alters HDL metabolism and could be responsible for the depressed levels of HDL that exist during chronic inflammatory diseases.