There is now considerable evidence that human serum contains an enzyme with both paraoxonase and arylesterase activities. The enzyme probably exists in two common isozymic forms with qualitatively distinctive properties. These isozymes differ particularly in their ratio of paraoxonase /arylesterase activities, one form having a ratio approximately seven times greater than the other. By measuring paraoxonase activity in the presence of 1 M NaCl, and arylesterase activity with phenylacetate under standard conditions, it is possible to classify individuals within one of the three phenotypes determined by a two-allele, single autosomal locus system at the ESA locus. These alleles are designated ESA*A and ESA*B. Pedigree analyses have also shown the anticipated Mendelian segregation of these traits within families. The frequencies of the ESA*A and ESA*B alleles in a sample population of unrelated Caucasian people in the United States were estimated to be 0.685 and 0.315, respectively, for the traits conferring relatively low and high paraoxonase activities. It still remains to be determined whether the distinctive phenotypes affect the degree of sensitivity or resistance to organophosphate agents, such as paraoxon. We do not know what additional functions these polymorphic enzymes may have in the metabolism of other compounds, particularly those of endogenous origin.