Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene; it is characterized by a high concentration of LDL, which frequently gives rise to tendon xanthomas and premature coronary artery disease (CAD). Individuals with heterozygous FH in China often exhibit a milder phenotype than those in other countries. The diagnosis of heterozygous FH relies on the clinical phenotype and this does not always permit unequivocal diagnosis of the disease. In the course of investigation of FH in a Chinese population sample, we found a family whose proband showed a markedly raised concentration of LDL cholesterol in plasma, and the presence of skin and tendon xanthomata. We used single-strand conformation polymorphism (SSCP) analysis to screen all the 18 exons and the exon-intron boundaries of the LDLR gene. One novel homozygous mutation, replacing T by C at nucleotide 850 in exon 6 was identified. This change substituted cysteine for arginine at codon 263 (C263R) of the LDLR. By means of mutant allele-specific amplification, we unequivocally diagnosed six heterozygotes with this novel mutation in the proband's family. forms of heterozygous FH are characterized by high serum LDL cholesterol levels, which are usually associated with premature coronary heart disease (CHD) and tendon xanthomas in early middle age, while homozygous FH individuals frequently suffer fatal CHD by their third decade (Goldstein et al. 1995). To date, more than 200 different mutations of the LDLR gene have been characterized worldwide (Hobbs et al. 1990; Hobbs et al. 1992; Varret et al. 1997). Chinese individuals with heterozygous FH are often recognized by virtue of their being parents of offspring with mutations in both alleles of the LDLR gene (Mak et al. 1998). Unlike their heterozygous parents, the Chinese homozygous FH patients are as severely affected, as are those elsewhere (Sun et al. 1994). In this article, we present an investigation of a Chinese family whose proband, with severe hypercholesterolemia, carried a novel mutation of the LDLR gene in a homozygous form, while the other six patients in the family, who carried this mutation in a heterozygous form, have a milder phenotype of FH. The main objective of our analysis was to delineate the full spectrum of mutations that underline FH in the Chinese population; our work represents a first step towards the implementation of nationwide DNA testing for this disease.