The novel compound NO-1886 ([4-(4-bromo-2-cyano-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester, CAS 133208-93-2) is a lipoprotein lipase (LPL) activator, and long term administration of NO-1886 protects against the development of experimental atherosclerosis in rats and rabbits. In the present experiments, the effects of this compound were examined in Watanabe heritable hyperlipidaemic (WHHL) rabbits, an animal model for familial hypercholesterolemia lacking low density lipoprotein (LDL) receptors. NO-1886 increased postheparin plasma LPL activity, resulting in a reduction of plasma triglycerides with concomitant elevation of HDL cholesterol in heterozygous WHHL rabbits. However, the compound did not cause any changes in plasma lipids and postheparin plasma LPL activity in homozygous WHHL rabbits. The different responses suggest that the effects of NO-1886 may be either mediated by LDL receptors, or that persistent exposure to extreme hypercholesterolemia might affect the cellular response to this particular compound in homozygous WHHL rabbits.