The human lipoprotein receptor related protein (LRP) binds and internalizes a diverse set of ligands, making LRP the most multifunctional endocytic receptor known. This is possible due to the large size, i.e., 600 kDa, of the receptor protein containing three clusters of putative ligand binding domains, each structurally comparable to the classical LDL receptor. Based on previous structural analysis of the human LRP1 gene (Van Leuven et al., 1994, Genomics, 24: 78-89), a strategy was developed to sequence the 89 exons of the LRP1 gene, including partial intron sequences. The gene was amplified from individual genomic DNA by long-range PCR, in 14 amplicons sized between 0.4 and 11 kb that were used as templates for 110 sequencing primers. In total, 48 mutations and intronic polymorphisms were identified. Two previously reported polymorphisms, i.e., in the promoter region and in exon 3, were precisely defined by sequencing. The first expressed mutation, i.e., an alanine to valine transition at position 217 of the LRP precursor protein, was detected on one allele in 2 of 33 individuals. Although the strategy is still subject to refinement, this approach is reported to allow others to analyze genetic differences in the human LRP1 gene, with particular reference to the recently reported association with late-onset Alzheimer disease.