Statin therapy is associated with changes in low-density, very low-density, and high- density lipoprotein metabolism. The effect of statin therapy on a minor high-density lipoprotein particle containing glycosylphosphatidylinositol-specific phospholipase D has not been examined. Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) has been implicated in triglyceride metabolism. A double-blind, crossover design comparing the effect of simvastatin (80 mg) and atorvastatin (80 mg) on serum lipid and glycosylphosphatidylinositol-specific phospholipase D levels was conducted in 13 patients with low high-density lipoproteins. Both statins reduced cholesterol, triglycerides, and apolipoprotein B and significantly lowered serum glycosylphosphatidylinositol-specific phospholipase D levels (16%). This statin effect seems to occur in the plasma compartment as neither statin altered GPI-PLD mRNA levels in HepG2 cells. Serum glycosylphosphatidylinositol-specific phospholipase D levels are regulated by statins and may represent an additional biochemical mechanism for affecting serum triglyceride levels.