The human apolipoprotein (apo) C-IV gene has been recently identified: it is closely linked to the promoter region of the apoC-II gene (Allan, C.M., D. Walker, J. Segrest, and J. M. Taylor. 1995. Genomics. 28: 291-300). To determine the effect of apoC-IV gene expression on lipoprotein metabolism, transgenic mice were generated using a human apoC-IV cDNA construct. Human apoC-IV was found associated with plasma lipoproteins (d < 1.21 g/ml), mainly in very low density lipoproteins (VLDL), and higher molecular mass isoforms were present, due to N-linked glycosylation and variable sialylation of apoC-IV. Human apoC-IV transgenic mice were hypertriglyceridemic compared to nontransgenic controls; the accumulated plasma triglycerides were present mainly in VLDL. There was little change in plasma cholesterol levels, although apoC-IV expression redistributed cholesterol to VLDL and larger particles in low density lipoprotein/large high density lipoprotein fractions. By immunoblot analysis, apoC-IV was not detected in normal adult human plasma or isolated plasma lipoproteins, a finding consistent with our previous observation of very low levels of human apoC-IV mRNA in human liver. However, our analysis of transgenic mice provides unequivocal evidence that human apoC-IV is a lipid-binding protein belonging to the apolipoprotein family and that it has the potential to alter lipoprotein metabolism.