1. Human serum paraoxonase (PON1) is a Ca2+-dependent 45-kDa glycoprotein that is associated with high density lipoprotein (HDL). 2. PON1 hydrolyzes organophosphate (OP) insecticides and nerve gases and is responsible for determining the selective toxicity of these compounds in mammals. 3. PON1 has two genetic polymorphisms giving rise to amino acid substitutions at positions 55 and 192. The position-192 polymorphism is the major determinant of the PON1 activity polymorphism. However, the position-55 polymorphism also modulates activity. 4. Genotyping individuals for both PON1 polymorphisms may provide a method for identifying those most at risk of OP poisoning. The effect of the PON1 polymorphisms on activity may explain why some Gulf War veterans have developed Gulf War syndrome and some have not, despite similar OP exposure. 5. PON1 may also be a determinant of resistance to the development of atherosclerosis by protecting lipoproteins against oxidative modification, perhaps by hydrolyzing phospholipid hydroperoxides. 6. The PON 1 polymorphisms are important in determining the capacity of HDL to protect low density lipoprotein against oxidative modification in vitro, which may explain the relation between the PON1 alleles and coronary heart disease in case-control studies.