The receptor for low density lipoprotein (LDL), the major cholesterol transport protein in plasma, is synthesized as a 120,000 dalton precursor that undergoes post-translational processing to form a mature cell surface glycoprotein with an apparent molecular weight of 160,000. We previously described seven mutations in the gene for the LDL receptor that disrupt the biosynthesis of the receptor, abolish its processing, or produce receptors of an abnormal size. In the current studies, we describe a new class of mutations that produce receptors whose processing is delayed, but not abolished. This class of mutations has been identified in a family with familial hypercholesterolemia (the O. family) and a strain of rabbits (WHHL rabbits) that manifests a clinical syndrome analogous to the human disease. The mutant receptors in the O. family and in WHHL rabbits are processed to the mature form at a markedly reduced rate, presumably owing to a delay in transport from the endoplasmic reticulum to the Golgi complex. Thus, the responsible mutations may have affected a signal for intracellular transport that is normally contained within the receptor molecule. In addition to their slow processing, the abnormal receptors bind LDL poorly. Thus, a single mutation can disrupt two functional domains of the LDL receptor molecule: the putative intracellular transport signal and the LDL binding site.