We studied an extended family of similar genetic and environmental background to determine whether there is a difference in response to statin therapy in those subjects with heterozygous familial hypercholesterolaemia (FH Afrikaner-1 (FH1) or FH Afrikaner-2 (FH2)) compared to those with familial defective apo B-100 (FDB), or both FH plus FDB. Fasting lipid profiles and Lp(a) levels were done on 18 members of the family and then repeated following 6 weeks of therapy with simvastatin 20 mg daily. Statin therapy reduced LDL-cholesterol (LDL-C) by 31% in those with FH (n = 7); 29.8% in FDB (n = 5) and 25.4% in those with both FDB and FH (n = 5). There was no response to statin therapy in the single subject with both FH1, FH2, as well as FDB. Lp(a) levels did not change significantly either within or between any of the groups following statin therapy (FH from 6.5 (1.2-72.3) to 5.3 (1.2-52.3), FDB from 6.1 (4.70-71) to 8.2 (5.7 79) and FDB plus FH from 4.5 (2.6-17.4) to 3.1 (1.9-24) mg/dl). Statins are equally effective in lowering LDL-C in related subjects with heterozygous FH, FDB or both FDB plus FH. The ability of statins to lower LDL-C in FDB is probably due to increased hepatic uptake of lipoprotein precursors of LDL that can bind via apo E receptors. Lp(a) concentration is not reduced by drugs that stimulate LDL receptor activity implying that LDL receptors do not contribute greatly to normal clearance of Lp(a) in hypercholesterolaemic subjects with defects in receptor-mediated endocytosis of LDL.