Phosphatidylinositol-glycan-specific phospholipase D (GPI-PLD) is a high-density lipoprotein-associated protein found on chromosome 6p22 that specifically hydrolyzes the inositol phosphate linkage in proteins anchored by phosphatidylinositol-glycans (PI-Gs). GPI-PLD is found in serum, liver, cerebrospinal fluid and in milk. The majority of plasma GPI-PLD appears to be specifically associated with a small, discrete and minor fraction of lipoproteins containing apoA-I and apoA-IV. Serum GPI-PLD activity is reduced over 75% in systemic inflammatory response syndrome and the downregulation of GPI-PLD could play an important role in the control of proinflammatory responses.