Human serum paraoxonase (PON1) associated with high density lipoprotein (HDL) has been postulated to have a role in protecting low density lipoprotein (LDL) against oxidative modification, which has led to the proposal that PON1 is an anti-atherogenic, anti-inflammatory enzyme. PON1 has two genetically determined polymorphic sites giving rise to amino-acid substitutions at positions 55 (L-->M) and 192 (R-->Q) and therefore 4 potential alloenzymes. We have examined the effects of these molecular polymorphisms on the ability of HDL to protect LDL from oxidative modification. HDL protected LDL from oxidative modification, whatever the combination of PON1 alloenzymes present in it. However, HDL from QQ/MM homozygotes was most effective at protecting LDL while HDL from RR/LL homozygotes was least effective. Thus after 6 h of co-incubation of HDL and LDL with Cu2+ PON1-QQ HDL retained 57 +/- 6.3% of its original ability to protect LDL from oxidative modification, while PON1-QR HDL retained less at 25.1 +/- 4.5% (P < 0.01) and PON1-RR HDL retained only 0.75 +/- 0.40% (P < 0.005). In similar experiments HDL from LL and LM genotypes retained 21.8 +/- 7.5% and 29.5 +/- 6.6% (P = NS), respectively, of their protective ability, whereas PON1-MM HDL maintained 49.5 +/- 5.3% (P < 0.01). PON1 polymorphisms may affect the ability of HDL to impede the development of atherosclerosis and to prevent inflammation.