Plasma phospholipid transfer protein mediates the net movement of phospholipids between lipoproteins and between lipid bilayers and high density lipoprotein. In this study, the mouse phospholipid transfer protein cDNA was cloned by reverse transcription polymerase chain reactions based on the cDNA sequence of human phospholipid transfer protein. The predicted amino acid sequence of mouse phospholipid transfer protein shows the protein to be 476 amino acids long and to have a sequence identity of 83% with that of human phospholipid transfer protein. Mouse plasma phospholipid transfer protein activity is 1.5-2 times that of human plasma phospholipid transfer protein activity. As in humans, mouse peripheral tissues displayed a higher abundance of phospholipid transfer protein mRNA than observed in central organs. The order of phospholipid transfer protein mRNA expression was as follows: lung > adipose tissue, placenta, testis > brain > muscle, heart, liver. We examined the regulation of phospholipid transfer protein expression by dietary cholesterol and by bacterial lipopolysaccharide. A high fat, high cholesterol diet caused a significant increase (35%) in plasma phospholipid transfer protein activity and a significant increase (18%) in high density lipoprotein phospholipids. This increased activity was accompanied by approximately 100% increase in phospholipid transfer protein mRNA in lung. After lipopolysaccharide injection, plasma phospholipid transfer protein activity was decreased by approximately 66%. This decrease in activity was associated with a similar decrease in phospholipid transfer protein mRNA in lung, adipose tissue, and liver. The decrease in plasma phospholipid transfer protein activity was also associated with a significant increase (17%) in high density lipoprotein phospholipid concentration. The opposite changes in phospholipids levels with lipopolysaccharide treatment and dietary cholesterol despite similarly increased high density lipoprotein phospholipids levels indicate that high density lipoprotein phospholipids levels are likely determined both by phospholipid transfer protein levels and by gradients of phospholipids concentration between high density lipoprotein and other phospholipids sources.