The low density lipoprotein receptor-related protein (LRP) has been proposed to mediate in concert with the LDL receptor (LDLR) the uptake of dietary lipoproteins into the hepatocytes. This hypothesis was tested by transient inactivation of LRP in vivo. Receptor-associated protein (RAP), a dominant negative regulator of LRP function, was transferred by an adenoviral vector to the livers of mice lacking LDLR (LDLR(-/-)). The inactivation of LRP by RAP was associated with a marked accumulation of chylomicron remnants in LDLR(-/-) mice and to a lesser degree in normal mice, suggesting that both LDLR and LRP are involved in remnant clearance.