Synthesis of the low density lipoprotein (LDL) receptor was studied by incubation of cultured human fibroblasts with 35S-methionine followed by immunoprecipitation with a monoclonal antireceptor antibody. The receptor was synthesized as a precursor with an apparent molecular weight of 120 kilodaltons (kd) that was converted to a mature form of 160 kd. This novel form of processing occurred 15-30 min after synthesis and did not appear to be due to the simple addition of N-linked oligosaccharide chains. Fibroblasts from a child with the phenotype of homozygous familial hypercholesterolemia showed a disruption in receptor processing. This child has two different mutant alleles at the LDL receptor locus. One allele, inherited from his heterozygous mother, produces an abnormal 120 kd protein that cannot be processed to the mature 160 kd form. The other allele, inherited from his heterozygous father, produces a receptor that is synthesized as an elongated 170 kd precursor which undergoes a 40 kd increase in molecular weight to form an abnormally large receptor of 210 kd.