A previous study of the low density lipoprotein (LDL) receptor gene haplotype distribution in 12 unrelated South African patients with homozygous familial hypercholesterolaemia indicated the existence of several different receptor gene mutations in this patient pool. We have now screened these subjects for large insertion or deletion mutations at their receptor gene loci by restriction fragment size analysis using the Southern blot hybridization technique. We have detected a hitherto undescribed 2.5-kb deletion, which mapped to the central region of the gene, and most likely includes all of exons 7 and 8. The deletion was confined to two of the three so-called coloured individuals in this racially divided sample. Both probands were homozygous for the deletion with a strong possibility of consanguinity in one of the families. Mendelian inheritance was shown in both families and all carriers detected manifested elevated plasma LDL cholesterol levels. The origin of the deletion is unclear but may have been present in the indigenous Khoisan population or have been brought to South Africa by early European or Indonesian settlers.